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Cited by 1,092DNA Repair MechanismsGenomics and Chromatin DynamicsCancer-related Molecular Pathways

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Open access
Polo, Sophie E., Jackson, Stephen P.·2011·Genes & Development
DOI 10.1101/gad.2021311PMC PMC3049283
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Abstract

Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells. Considerable advances have also been made in understanding the underlying molecular mechanisms for these events, with post-translational modifications of DDR factors being shown to play prominent roles in controlling the formation of foci in response to DNA-damaging agents. We review these regulatory mechanisms and discuss their biological significance to the DDR.

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Written from the paper’s full text.

TL;DR

This review synthesizes how DNA damage response proteins dynamically assemble and disassemble at DNA single- and double-strand breaks, with emphasis on post-translational modifications as central regulators of foci formation and turnover. It surveys methodologies for detecting these dynamics and discusses the evolutionary conservation, biological significance, and disease relevance of DDR foci.

Key findings

  • DDR proteins accumulate at breaks in sequential, spatially organized foci: SSB factors reach maximal accumulation within 1–2 min via PARylation; NHEJ factors are recruited within seconds and normally dissociate within 2 h, whereas HR factors show delayed and persistent recruitment.
  • γH2AX spreads from DSBs over up to 100 kb in yeast versus several megabases in mammals; mammalian cells form 20–40 DSB foci per nucleus per Gray of radiation; 10–20 DSBs can elicit G2 arrest in human cells, and very few or even a single unrepaired DSB can trigger p53-dependent G1 arrest in human cells or cell death in yeast.
  • Post-translational modifications—phosphorylation, ubiquitylation, sumoylation, methylation, acetylation, and PARylation—create docking sites or alter residence times at damage sites; examples include MDC1/BRCT binding to γH2AX, RNF8/RNF168-dependent ubiquitylation, PIAS1/PIAS4 sumoylation of 53BP1 and BRCA1, Tudor-domain recognition of methylated histones, and PAR-dependent recruitment of XRCC1 and APLF.
  • DDR foci are proposed to concentrate factors, amplify signaling, stabilize broken DNA ends, and coordinate repair with transcription and replication; defects in focus regulators are linked to genome instability disorders and cancer, and γH2AX foci are noted as a promising diagnostic tool.

Methods

  • Narrative review, not primary research; focuses on cellular responses to SSBs and DSBs in eukaryotic cells, with emphasis on mammalian systems.
  • Evidence base consists of published literature and cited studies; includes tables cataloging DNA strand break repair/signaling factors and chromatin-associated factors recruited to or dissociating from damaged chromatin.
  • Main analysis is a synthesis of spatiotemporal dynamics, molecular mechanisms of DDR protein assembly/disassembly, post-translational modification control, and functional/medical significance.

Limitations

  • Stated: the authors apologize for not citing some work, having elected not to cite certain studies to keep the review to a reasonable length; they also list remaining challenges, including identifying more DDR components, understanding how PTMs are erased and how they cross-talk, and determining how DDR signaling/repair is influenced by cell physiology, disease, cell type, and tissue.
  • Evident: as a narrative review, it lacks systematic search criteria, quantitative meta-analysis, and primary experimental validation; coverage is selective and emphasizes mammalian systems and selected model organisms.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1101/gad.2021311

Cites

373 of 373 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 335 cited sources checked · 0 supported · 0 flagged

  • Premisecitation
    § Polo and Jackson

    Broken DNA ends juxtaposed by DNA-PK are acted on by Artemis, PNK, Aprataxin, and APLF before ligation by XLF-XRCC4-LigaseIV.

    “Broken DNA ends juxtaposed by DNA-PK are then acted on by factors such as the nuclease Artemis, polynucleotide kinase (PNK), Aprataxin, and APLF (Aprataxin and PNK-like factor) before being ligated by the XLF-XRCC4 (X-ray crosscomplementing-4)-LigaseIV complex (Table 1; Lieber and Wilson 2010).”
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  • Premisecitation
    § Polo and Jackson

    Resection comprises 5'-to-3' nucleolytic processing of DNA ends by the MRN complex in conjunction with CtIP, RECQ helicases, Exo1, and Dna2.

    “Resection comprises the 5 9 -to-3 9 nucleolytic processing of DNA ends by the MRN complex (Rupnik et al. 2010) in conjunction with auxiliary factors including CtIP, RECQ family helicases, and the nucleases Exo1 and Dna2 (Zou and Elledge 2003; Bernstein and Rothstein 2009; Mimitou and Symington 2009; Huertas 2010; Longhese et al. 2010; You and Bailis 2010).”
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  • Premisecitation
    § Polo and Jackson

    After DNA polymerases and Ligase I, helicase and resolvase enzymes mediate cleavage and resolution of HR intermediates to yield intact repaired DNA.

    “After the actions of DNA polymerases and DNA end ligation by Ligase I, DNA helicase and resolvase enzymes then mediate the cleavage and resolution of HR intermediates to yield intact, repaired DNA molecules (Table 1; Mazon et al. 2010).”
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  • Premisecitation
    § Responses to DNA breaks in a physiological context

    ATM mediates local inhibition of RNA polymerase I- and II-dependent transcription at sites of DNA breaks in human cells.

    “Indeed, ATM has been reported to mediate local inhibition of both RNA polymerase I- and II-dependent transcription at sites of DNA breaks in human cells (Kruhlak et al. 2007; Shanbhag et al. 2010).”
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  • Premisecitation
    § Responses to DNA breaks in a physiological context

    Chromatin is dynamic and can be modulated by DNA methylation, histone variants, histone post-translational modifications, and ATP-dependent remodeling.

    “Although chromatin acts as a physical barrier to the detection and repair of DNA lesions, it is also a dynamic structure that can be modulated by DNA methylation (Kulis and Esteller 2010), incorporation of histone variants (Bernstein and Hake 2006), histone post-translational modifications (Kouzarides 2007), and nucleosome repositioning by ATP-dependent remodeling complexes (Clapier and Cairns 200”
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    Premisecitation
    § Polo and Jackson

    Alternative end-joining pathways often rely on terminal microhomologies and involve factors also functioning in HR or SSBR, such as MRN, PARP-1, XRCC1, and DNA Ligase I or III.

    “These alternative end-joining pathways often rely on terminal microhomologies for the joining reaction, and involve certain factors that also function in HR or SSB repair (SSBR), such as the MRE11RAD50-NBS1 (MRN) complex, poly(ADP-ribose) polymerase-1 (PARP-1), XRCC1, and DNA Ligase I or III (McVey and Lee 2008).”
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    Premisecitation
    § Polo and Jackson

    NHEJ is the prevalent DSB repair pathway in higher eukaryotes and mediates direct ligation of broken DNA ends with minimal end processing.

    “NHEJ, which is the prevalent DSB repair pathway in higher eukaryotes, essentially mediates the direct ligation of broken DNA ends, and usually involves minimal DNA end processing.”
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    Interpretationcitation
    § Responses to DNA breaks in a physiological context

    Transcriptional inhibition at DNA breaks is accompanied by clearance of active RNA polymerases from damage sites, indicating that protein dynamics at DNA breaks operate in both directions: DDR factors are recruited while other factors dissociate.

    “Such transcriptional inhibition is accompanied by the clearance of active RNA polymerases from damage sites, highlighting that protein dynamics at DNA breaks operate in both directions: While DNA damage signaling and repair factors are recruited to DNA breaks, other factors dissociate (Fig. 1).”
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    Premisereasoning
    § Polo and Jackson

    In most eukaryotes, SSBs are initially detected by PARP-1, whose binding triggers poly(ADP-ribosyl)ation of nuclear proteins including itself.

    “In most eukaryotes, SSBs are initially detected by PARP-1, whose binding to DNA breaks triggers poly-(ADP-ribosyl)ation of numerous nuclear proteins, including itself.”
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    Premisecitation
    § Responses to DNA breaks in a physiological context

    Chromatin remodeling complexes and histone chaperones have been linked to histone mobilization, histone variant replacement, and new histone deposition at sites of DNA breaks.

    “In particular, chromatin remodeling complexes and histone chaperones have been linked to histone mobilization (Tsukuda et al. 2005; Kent et al. 2007; Shim et al. 2007; Xu et al. 2010), histone variant replacement (Kusch et al. 2004; PapamichosChronakis et al. 2006; Heo et al. 2008), and new histone deposition (Polo et al. 2006; Chen et al. 2008) at sites of DNA breaks.”
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    Premisecitation
    § Signaling of DNA breaks

    The MRN sensor complex detects DSBs, and RPA signals accumulation of ssDNA resulting from DNA damage processing.

    “Of particular note are the MRN sensor complex that detects DSBs (Lavin 2007), and RPA that signals the accumulation of ssDNA resulting from DNA damage processing.”
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    Premisecitation
    § Polo and Jackson

    Poly(ADP-ribosyl)ation promotes binding of XRCC1, which acts as a molecular scaffold for downstream SSBR components involved in end-processing, gap filling, and ligation.

    “These modifications in turn promote the binding of XRCC1, which acts as a molecular scaffold for downstream SSBR components involved in end-processing, gap filling, and ligation (Table 1).”
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    Premisecitation
    § Polo and Jackson

    NHEJ can operate throughout the cell cycle without template DNA and is often mutagenic because deletions or insertions can be induced at repair sites.

    “In contrast, NHEJ can operate throughout the cell cycle without the need for template DNA, and is often mutagenic because deletions or insertions can be induced at sites of repair (Lieber 2010).”
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    Premisecitation
    § Polo and Jackson

    SSBs are toxic because they can block DNA replication and transcription, and SSBR defects are associated with hereditary neurodegenerative diseases.

    “Although not as harmful as DSBs, SSBs are toxic to the cell, as they can block DNA replication and transcription, and, indeed, SSBR defects are associated with several hereditary neurodegenerative diseases (Caldecott 2008).”
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    Premisecitation
    § Signaling of DNA breaks

    MRN contributes to recruitment and activation of ATM, while RPA recruits ATR via ATRIP.

    “MRN contributes to the recruitment and activation of the apical DDR kinase ATM (ataxia telangiectasia mutated) (Uziel et al. 2003; Falck et al. 2005; Lee and Paull 2005), while RPA recruits the ATR (ATM and rad3-related) kinase via its partner protein, ATRIP (ATR-interacting partner) (Cortez et al. 2001; Rouse and Jackson 2002; Zou and Elledge 2003).”
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    Premisecitation
    § Polo and Jackson

    In NHEJ, DNA ends are first bound by Ku70/Ku80, which recruits and activates DNA-PKcs to form the DNA-PK holoenzyme.

    “In NHEJ, DNA ends are first bound by the Ku70/Ku80 heterodimer, which recruits and activates the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK holoenzyme (Gottlieb and Jackson 1993).”
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    Premisecitation
    § Polo and Jackson

    DSB resection is an important regulatory step determining the choice between HR and NHEJ; it is required for HR but not NHEJ.

    “An important regulatory step that determines the choice between the two main DSB repair pathways is the process of DSB resection, which is required for HR but not NHEJ.”
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    Premisecitation
    § Spatial organization of DDR foci

    Chk1 and Chk2 effector kinases become phosphorylated at damage sites but then quickly dissociate and distribute throughout the nucleus.

    “the Chk1 and Chk2 effector kinases, which become phosphorylated at damage sites but then quickly dissociate and distribute throughout the nucleus (Lukas et al. 2003; Smits et al. 2006).”
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    Premisecitation
    § Temporal organization of DDR foci

    Recruitment of DDR factors to SSBs is very rapid and transient, reaching maximal accumulation within 1-2 min, due to its dependency on PARylation, which is a relatively short-lived protein modification.

    “For instance, the recruitment of DDR factors to SSBs is very rapid and transient (Mortusewicz et al. 2007), reaching maximal accumulation within 1-2 min, due to its dependency on poly(ADP-ribosyl)ation (PARylation), which is a relatively short-lived protein modification (Gagne et al. 2006; Hakme et al. 2008).”
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    Premisecitation
    § Spatial organization of DDR foci

    The barrier to γH2AX focus formation in heterochromatin is relieved in S phase by DNA replication, and replication stress-associated γH2AX is detected in heterochromatin regions.

    “This barrier is relieved in S phase, however, by DNA replication, and replication stress-associated g H2AX is also detected in heterochromatin regions (Chadwick and Lane 2005; Cowell et al. 2007; Rozenzhak et al. 2010; Szilard et al. 2010)”
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    • cites Rozenzhak et al. 2010

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    Interpretationnone given
    § Spatiotemporal dynamics of DDR protein assembly/disassembly at DNA breaks

    A wealth of studies have highlighted the tight spatiotemporal coordination of DDR protein assembly and disassembly at DNA breaks.

    “As described below, a wealth of studies have highlighted the tight spatiotemporal coordination of DDR protein assembly and disassembly at DNA breaks.”
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    Premisecitation
    § Spatial organization of DDR foci

    In budding yeast, DDR foci are highly mobile and coalesce into repair centers.

    “In budding yeast, DDR foci are highly mobile and coalesce into repair centers (Lisby et al. 2003)”
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    Interpretationnone given
    § Spatial organization of DDR foci

    DDR proteins initially accumulate at DSB sites and then spread at distance via a positive feedback loop involving MDC1, which binds γH2AX, the MRN complex, and ATM kinase, which phosphorylates additional H2AX molecules further away from the break site.

    “DDR proteins initially accumulate at DSB sites and then spread at distance via a positive feedback loop involving MDC1, which binds g H2AX, the MRN complex, and ATM kinase, which phosphorylates additional H2AX molecules further away from the break site.”
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    Premisecitation
    § Temporal organization of DDR foci

    The accumulation kinetics of factors involved in DSB signaling is a two-stage process: initial recruitment occurs independently of H2AX phosphorylation, followed by sustained DDR factor retention in a γH2AX-dependent manner.

    “The accumulation kinetics of factors involved in DSB signaling has also been studied in great detail, and has been described as a two-stage process in which initial recruitment occurs independently of H2AX phosphorylation, followed by sustained DDR factor retention in a g H2AXdependent manner (Celeste et al. 2003b; Yuan et al. 2010).”
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    Premisecitation
    § Spatial organization of DDR foci

    Factors accumulating at DSB sites do not always colocalize perfectly; two classes of DDR proteins are distinguishable based on spatial distributions: those present directly at damage sites coating ssDNA from DSB resection, and those associated with DSB-flanking chromatin.

    “factors accumulating at DSB sites do not always colocalize perfectly, with two classes of DDR proteins being readily distinguishable based on their spatial distributions (Fig. 3): those present directly at damage sites, coating ssDNA resulting from DSB resection, and those associated with DSB-flanking chromatin (Bekker-Jensen et al. 2006).”
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    Premisecitation
    § Polo and Jackson

    The number of focus-positive cells and foci per cell increase dose-dependently in mammalian cells (e.g., 20-40 DSB foci per nucleus per Gray), and focus number and size change over time after DNA damage.

    “Importantly, the number of focus-positive cells and the number of foci per cell each increase in a dose-dependent manner in mammalian cells (for example, 20-40 DSB foci per nucleus per Gray of radiation for a mammalian cell), and focus number and size also change over time after DNA damage induction (van Veelen et al. 2005).”
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    Premisenone given
    § Spatial organization of DDR foci

    Factors involved in ATR signaling accumulate proximal to the break site on ssDNA generated by DNA end resection, while ATM signaling factors localize on flanking chromatin regions.

    “Factors involved in ATR signaling accumulate proximal to the break site on ssDNA generated by DNA end resection, while ATM signaling factors localize on flanking chromatin regions.”
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    Premisecitation
    § Temporal organization of DDR foci

    Factors involved in DSB repair by NHEJ are recruited within seconds upon break formation and normally dissociate within 2 h.

    “Factors involved in DSB repair by NHEJ are also recruited within seconds upon break formation and normally dissociate within 2 h”
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    Premisereasoning
    § Direct recognition of DNA breaks by DDR factors

    Among the first proteins recruited to DNA breaks are those able to directly recognize DNA breaks; such factors bind broken DNA in a sequence-independent manner and act as molecular sensors of DNA breaks.

    “Among the first proteins recruited to DNA breaks are those able to directly recognize DNA breaks. Such factors bind broken DNA in a sequence-independent manner, and thus act as molecular sensors of DNA breaks.”
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    Premisecitation
    § Direct recognition of DNA breaks by DDR factors

    DNA binding by PARP-1 is mediated via N-terminal zinc finger domains, and by PARP-2 via a basic N-terminal domain.

    “DNA binding is mediated via N-terminal zinc finger domains in PARP-1 (Menissier-de Murcia et al. 1989), and a basic N-terminal domain in PARP-2 (Ame et al. 1999).”
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    Premisecitation
    § Dynamics of DNA damage foci

    Resection has been reported in G1 at sites of IR-induced breaks in budding yeast, although the rate of resection is higher in S phase and lesions appear to become recognized by the HR machinery only upon entry into S phase.

    “In contrast, resection has been reported in G1 at sites of IR-induced breaks in budding yeast, although the rate of resection is higher in S phase and lesions appear to become recognized by the HR machinery only upon entry into S phase (Barlow et al. 2008).”
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    Premisecitation
    § Direct recognition of DNA breaks by DDR factors

    RPA directs the recruitment of the Rad9-Rad1-Hus1 (9-1-1) complex, a heterotrimeric ring structurally similar to PCNA, which is loaded onto ssDNA-dsDNA junctions by an RFC-like clamp loader.

    “RPA in turn directs the recruitment of the Rad9-Rad1-Hus1 (9-1-1) complex, a heterotrimeric ring that is structurally similar to the replicative sliding clamp PCNA (proliferating cell nuclear antigen) and is loaded onto ssDNA-dsDNA junctions by an RFC (replication factor C)-like clamp loader (ParrillaCastellar et al. 2004).”
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    Premisecitation
    § Direct recognition of DNA breaks by DDR factors

    The MRN complex binds DSBs via a globular head region comprised of MRE11 together with joined RAD50 ATPase domains, with MRE11 dimerization ensuring stable DNA binding, and RAD50 dimerization tethering DNA ends together.

    “while the MRN complex binds DSBs via a globular head region comprised of MRE11 together with joined RAD50 ATPase domains, with MRE11 dimerization ensuring stable DNA binding, and RAD50 dimerization tethering DNA ends together (de Jager et al. 2001; Williams et al. 2008).”
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    Premisecitation
    § DDR protein assembly mediated by protein-protein interactions

    ATR is recruited to resected DSBs via its interacting partner ATRIP, which binds to RPA-coated ssDNA in human cells.

    “In contrast, ATR is recruited to resected DSBs via its interacting partner, ATRIP (Cortez et al. 2001), which binds to RPA-coated ssDNA in human cells, a mechanism that is conserved for yeast orthologs of these factors (Rouse and Jackson 2002; Zou and Elledge 2003; Ball et al. 2007).”
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    Premisecitation
    § Dynamics of DNA damage foci

    Cell cycle control of DNA resection and HR relies on cell cycle-regulated expression of key factors such as CtIP and BRCA1, and is also governed by cyclin-dependent kinases (Cdks) that phosphorylate evolutionarily conserved residues in CtIP.

    “Recent work has shown that cell cycle control of DNA resection and HR relies on cell cycleregulated expression of key factors such as CtIP and BRCA1, and is also governed by cyclin-dependent kinases (Cdks) that phosphorylate evolutionarily conserved residues in CtIP (Huertas et al. 2008; Huertas and Jackson 2009; You and Bailis 2010).”
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    Premisecitation
    § DDR protein assembly mediated by protein-protein interactions

    XRCC1 and XRCC4 act as scaffold proteins, promoting the accumulation of repair factors at SSBs and DSBs, respectively.

    “Similarly, XRCC1 and XRCC4 act as scaffold proteins, promoting the accumulation of repair factors at SSBs and DSBs, respectively (Fig. 5; Mortusewicz et al. 2008).”
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    Premisecitation
    § Direct recognition of DNA breaks by DDR factors

    The Ku70-Ku80 heterodimer and the MRN complex are DSB sensors that display direct binding to DNA ends in vitro, and are among the earliest factors to bind to DSBs in vivo.

    “Similarly, the Ku70Ku80 heterodimer and the MRN complex are DSB sensors that display direct binding to DNA ends in vitro (Mimori and Hardin 1986; de Jager et al. 2001), and are among the earliest factors to bind to DSBs in vivo (Lisby et al. 2004; Kim et al. 2005).”
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    Interpretationcitation
    § Direct recognition of DNA breaks by DDR factors

    Unlike RPA, SOSS proteins appear to form DDR foci independently of cell cycle stage in a CtIP-independent manner, and recent work suggests that they could function upstream of MRN.

    “Unlike RPA, these proteins appear to form DDR foci independently of cell cycle stage in a CtIP-independent manner, and recent work suggests that they could function upstream of MRN (Richard et al. 2010).”
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    Premisenone given
    § DDR protein assembly mediated by protein-protein interactions

    Such control mechanisms rely heavily on phosphorylation, and are also regulated by ubiquitylation, sumoylation, methylation, acetylation, and PARylation.

    “While such control mechanisms rely heavily on phosphorylation, a major breakthrough in recent years has been the realization that they are also regulated by other post-translational modifications, including ubiquitylation, sumoylation, methylation, acetylation, and PARylation.”
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    Interpretationreasoning
    § Polo and Jackson

    This phospho-dependent dissociation mechanism seems critical for efficient repair of DNA damage, and thus potentially contributes to the transition from DNA damage signaling to repair.

    “This phospho-dependent dissociation mechanism seems critical for efficient repair of DNA damage, and thus potentially contributes to the transition from DNA damage signaling to repair.”
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    Interpretationreasoning
    § DDR protein assembly mediated by protein-protein interactions

    The building of multiprotein assemblies at DNA breaks is tightly controlled, much of this achieved by posttranslational protein modifications that promote the recruitment or dissociation of DDR factors or regulate their residence times at damage sites.

    “As can be expected for a crucial cellular process, the building of multiprotein assemblies at DNA breaks is tightly controlled. Much of this is achieved by posttranslational protein modifications (Fig. 6) that promote the recruitment or dissociation of DDR factors or regulate their residence times at damage sites.”
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    Interpretationcitation
    § Polo and Jackson

    This HP1 delocalization disrupts HP1 interactions with heterochromatin marks, and could thereby contribute to relieving the inhibitory effect of chromatin compaction on the DDR.

    “This disrupts HP1 interactions with heterochromatin marks, and could thereby contribute to relieving the inhibitory effect of chromatin compaction on the DDR.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Polo and Jackson

    This NBS1 module mediates binding to MDC1 phospho-SDTD repeats in human cells, binds the phosphorylated CtIP ortholog in fission yeast, and interacts with the phosphorylated XRCC4 ortholog in budding yeast.

    “Interestingly, while this module mediates binding to MDC1phospho-SDTDrepeats in human cells, it binds the phosphorylated CtIP ortholog in fission yeast and interacts with the phosphorylated XRCC4 ortholog in budding yeast (Matsuzaki et al. 2008; Palmbos et al. 2008; Lloyd et al. 2009; Williams et al. 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Matsuzaki et al. 2008

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    • cites Palmbos et al. 2008

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    • cites Lloyd et al. 2009

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    Premisecitation
    § Key roles for protein phosphorylation in the assembly of DDR foci

    Once bound to γH2AX, MDC1 acts as a loading platform for other DDR components, with many of these interactions also being phospho-dependent.

    “Once bound to g H2AX, MDC1 in turn acts as a loading platform for other DDR components, with many of these interactions also being phospho-dependent (Jungmichel and Stucki 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jungmichel and Stucki 2010

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    Premisecitation
    § Key roles for protein phosphorylation in the assembly of DDR foci

    Several hundreds of phosphorylated targets in the DDR have already been identified by mass spectrometry-based screens.

    “with several hundreds of phosphorylated targets having already been identified by mass spectrometry-based screens (Matsuoka et al. 2007; Bennetzen et al. 2010; Bensimon et al. 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Matsuoka et al. 2007

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    • cites Bennetzen et al. 2010

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    • cites Bensimon et al. 2010

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    Premisecitation
    § Key roles for protein phosphorylation in the assembly of DDR foci

    ATM-dependent phosphorylation of MDC1 on TQXF motifs creates binding sites for the FHA domain of the ubiquitin E3 ligase RNF8, which in turn promotes the focal accumulation of 53BP1 and BRCA1 at DSB sites.

    “For instance, ATM-dependent phosphorylation of MDC1 on Thr-Gln-X-Phe (TQXF) motifs creates binding sites for the FHA domain of the ubiquitin E3 ligase RNF8 (Ring finger protein 8), which in turn promotes the focal accumulation of 53BP1 and BRCA1 at DSB sites (Huen et al. 2007; Kolas et al. 2007; Mailand et al. 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Huen et al. 2007

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    • cites Kolas et al. 2007

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    • cites Mailand et al. 2007

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    Premisecitation
    § Polo and Jackson

    Both RNF8 and RNF168 function with the ubiquitin-conjugating E2 enzyme UBC13, and the ubiquitin E3 ligase HERC2 promotes RNF8 assembly with UBC13.

    “Notably, both RNF8 and RNF168 function with the ubiquitin-conjugating E2 enzyme UBC13, and the ubiquitin E3 ligase HERC2 was shown recently to promote RNF8 assembly with UBC13,asopposed to other ubiquitin E2 enzymes (BekkerJensen et al. 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bekker-Jensen et al. 2010

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    Premisecitation
    § Polo and Jackson

    HERC2 stabilizes RNF168 protein levels, thereby regulating ubiquitin-dependent retention of 53BP1 and BRCA1 at DSB sites.

    “Additionally, HERC2 stabilizes RNF168 protein levels, thereby regulating ubiquitin-dependent retention of 53BP1 and BRCA1 at DSB sites (Bekker-Jensen et al. 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bekker-Jensen et al. 2010

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    Premisecitation
    § Polo and Jackson

    RNF8-dependent recruitment factors include checkpoint mediators 53BP1, BRCA1, and PTIP; the ubiquitin ligase RAD18; and the histone chaperone NPM1.

    “These factors include the checkpoint mediators 53BP1, BRCA1, and PTIP (Pax2 transactivation domain interaction protein) (Huen et al. 2007; Kolas et al. 2007; Mailand et al. 2007; Wang and Elledge 2007; Doil et al. 2009; Gong et al. 2009; Stewart et al. 2009; Wu et al. 2009a,b); the ubiquitin ligase RAD18, which elicits postreplication repair of damaged DNA (Huang et al. 2009b); and the histone”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Huen et al. 2007

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    • cites Kolas et al. 2007

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    • cites Mailand et al. 2007

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    Premisecitation
    § Polo and Jackson

    Sumoylation of human RPA70 enhances its binding to Rad51 and facilitates Rad51 recruitment to DNA damage foci.

    “the human RPA70 subunit, whose sumoylation enhances its binding to Rad51 and facilitates Rad51 recruitment to DNA damage foci (Dou et al. 2010)”
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    • cites Dou et al. 2010

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    Premisecitation
    § Polo and Jackson

    RNF8-dependent ubiquitylation is further amplified by the RNF168 ubiquitin ligase, which is mutated in patients suffering from RIDDLE syndrome.

    “RNF8-dependent ubiquitylation is further amplified by the RNF168 ubiquitin ligase, which is mutated in patients suffering from RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties) (Doil et al. 2009; Pinato et al. 2009; Stewart et al. 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Doil et al. 2009

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    • cites Pinato et al. 2009

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    • cites Stewart et al. 2009

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    Premisecitation
    § Polo and Jackson

    The ubiquitin E3 ligase RNF8 ubiquitylates histones H2A, H2B, and H2AX, and possibly other substrates, promoting the focal recruitment of various DDR factors to sites of DNA strand breaks.

    “Besides work on BRCA1/BARD1, much attention has focused on ubiquitylation of histones H2A, H2B, and H2AX, and possibly other substrates by the ubiquitin E3 ligase RNF8, which promotes the focal recruitment of various DDR factors to sites of DNA strand breaks.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Huen et al. 2007

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    • cites Kolas et al. 2007

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    • cites Mailand et al. 2007

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    Premisecitation
    § Sumoylation controls DDR focus assembly

    SUMO conjugation takes place at DNA break sites in mammalian cells, and the ensuing accumulation of sumoylated proteins in these regions promotes both protein ubiquitylation at DNA break sites and DDR focus formation.

    “Furthermore, it was established recently that SUMO conjugation takes place at DNA break sites in mammalian cells, and that the ensuing accumulation of sumoylated proteins in these regions then promotes both protein ubiquitylation at DNA break sites and DDR focus formation (Galanty et al. 2009; Morris et al. 2009).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Galanty et al. 2009

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    • cites Morris et al. 2009

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    Premisecitation
    § Polo and Jackson

    PTIP focus formation is BRCT-dependent, suggesting a requirement for phosphorylation.

    “Indeed, PTIP focus formation is BRCT-dependent (Manke et al. 2003), suggesting a requirement for phosphorylation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Manke et al. 2003

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    Premisecitation
    § Polo and Jackson

    One identified BRCA1 ubiquitylation target is CtIP, with BRCA1-mediated ubiquitylation promoting CtIP binding to damaged chromatin.

    “While few BRCA1 ubiquitylation targets have been identified so far, one of these is CtIP, with BRCA1-mediated ubiquitylation promoting CtIP binding to damaged chromatin (Yu et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yu et al. 2006

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    Premisecitation
    § PARylation targets DDR proteins to DNA breaks

    PARylation can promote protein dissociation from DNA damage, as shown for FACT, which is released from damaged chromatin upon PARylation of its Spt16 subunit.

    “PARylation can also promote protein dissociation from DNA damage, as shown for the histone chaperone FACT (facilitates chromatin transcription), which is released from damaged chromatin upon PARylation of its Spt16 subunit (Huang et al. 2006; Heo et al. 2008)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Huang et al. 2006

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    • cites Heo et al. 2008

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    Premisecitation
    § Focus disassembly by reversion of post-translational modifications

    Resumption of cell cycle progression following DNA repair requires switching off the DDR, which involves disassembly of DDR foci.

    “Resumption of cell cycle progression following DNA repair requires switching off the DDR (Bartek and Lukas 2007), which involves disassembly of DDR foci.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bartek and Lukas 2007

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    Premisecitation
    § PARylation targets DDR proteins to DNA breaks

    PARylation imposed by PARP1 and PARP2 in response to DNA breaks in mammalian cells is one of the earliest events in the DDR but is quickly removed by PARG.

    “Imposed by PARP1 and PARP2 enzymes in response to DNA breaks in mammalian cells, where it has been most thoroughly studied, PARylation is one of the earliest events in the DDR but is quickly removed by the action of PARG (PAR glycohydrolase) (Gagne et al. 2006; Hakme et al. 2008; Krishnakumar and Kraus 2010)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gagne et al. 2006

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    • cites Hakme et al. 2008

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    • cites Krishnakumar and Kraus 2010

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    Premisecitation
    § Protein acetylation regulates DDR factor assembly

    SIRT6-dependent deacetylation of CtIP in response to DSBs stimulates RPA and RAD51 focus formation, promoting ATR signaling and DSB repair by HR.

    “SIRT6-dependent deacetylation of the CtIP protein in response to DSBs stimulates RPA and RAD51 focus formation, thus promoting ATR signaling and DSB repair by HR (Kaidi et al. 2010)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kaidi et al. 2010

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    Premisecitation
    § PARylation targets DDR proteins to DNA breaks

    PARP proteins comprise a large family broadly distributed among eukaryotes, several members of which have clearly identified DDR functions.

    “PARP proteins comprise a large family broadly distributed among eukaryotes, several members of which have clearly identified DDR functions (Citarelli et al. 2010)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Citarelli et al. 2010

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    Premisecitation
    § PARylation targets DDR proteins to DNA breaks

    PARylation is catalyzed by PARP enzymes.

    “The covalent modification of proteins with ADP-ribose polymers, a process known as PARylation, is catalyzed by PARP enzymes (Hakme et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hakme et al. 2008

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    Premisecitation
    § Polo and Jackson

    H2AX-deficient mice are viable and show only partial DDR defects, but are growth-retarded and display increased cancer predisposition in the context of oncogenic mutations.

    “while H2AX-deficient mice are viable and show only partial DDR defects, they are growth-retarded and display increased cancer predisposition in the context of oncogenic mutations (Bassing et al. 2002, 2003; Celeste et al. 2002, 2003a)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bassing et al. 2002, 2003

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    • cites Celeste et al. 2002, 2003a

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    Premisecitation
    § Polo and Jackson

    Tudor domains of human 53BP1 are found in yeast 53BP1 orthologs and associate with similar or identical methylated histone residues in all species examined.

    “the Tudor domains of human 53BP1 are also found in yeast 53BP1 orthologs, and associate with similar or identical methylated histone residues in all species examined (Huyen et al. 2004; Sanders et al. 2004; Botuyan et al. 2006; Grenon et al. 2007; Greeson et al. 2008; Oda et al. 2010)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Huyen et al. 2004

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    • cites Sanders et al. 2004

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    • cites Botuyan et al. 2006

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    Premisecitation
    § Polo and Jackson

    Single-knockout mice for PARP-1 or PARP-2 are viable but display increased genomic instability and hypersensitivity to DNA-damaging agents, while double knockout is early embryonic-lethal.

    “Single-knockout mice for PARP-1 or PARP-2 are viable, although they display increased genomic instability and hypersensitivity to DNAdamaging agents, while the double knockout is early embryonic-lethal (Wang et al. 1995; de Murcia et al. 1997; Masutani et al. 1999; Menissier de Murcia et al. 2003)”
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    • cites de Murcia et al. 1997

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    • cites Masutani et al. 1999

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    Premisecitation
    § Focus disassembly by reversion of post-translational modifications

    H2AX dephosphorylation can take place on chromatin in human cells or after histone eviction from chromatin in yeast.

    “can take place on chromatin, as reported in human cells (Chowdhury et al. 2005, 2008; Nakada et al. 2008), or after histone eviction from chromatin in yeast (Keogh et al. 2006)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chowdhury et al. 2005, 2008

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    • cites Nakada et al. 2008

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    • cites Keogh et al. 2006

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Polo and Jackson

    MRN, RNF8, and RNF168 have been identified as prominent targets during viral infection.

    “MRN, RNF8, and RNF168 have been identified as prominent targets during viral infection (Carson et al. 2009; Lilley et al. 2010)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carson et al. 2009

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    • cites Lilley et al. 2010

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    Premisecitation
    § Polo and Jackson

    Checkpoint kinases occur in virtually all eukaryotes studied and appear to rely on highly conserved mechanisms for their recruitment and activation in response to DNA breaks.

    “the checkpoint kinases, which occur in virtually all eukaryotes studied and appear to rely on highly conserved mechanisms for their recruitment and activation in response to DNA breaks (Falck et al. 2005; Stracker et al. 2009)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Falck et al. 2005

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    • cites Stracker et al. 2009

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    Premisecitation
    § Conclusions and future directions

    Immunodetection of γH2AX foci, which indirectly measure DSB formation and repair, is showing promise as a sensitive diagnostic tool to detect cancer cells and monitor cancer progression and assess responses to treatment.

    “the immunodetection of g H2AX foci, which indirectly measure DSB formation and repair, is showing promise as a sensitive diagnostic tool to detect cancer cells and also monitor cancer progression and assess responses to treatment (Bonner et al. 2008; Mah et al. 2010)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bonner et al. 2008

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    • cites Mah et al. 2010

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    Premisecitation
    § Structural and regulatory functions of DDR foci

    SMC proteins, including cohesins, are recruited to chromosomes in response to DSBs in budding yeast, where they facilitate DSB repair by HR by maintaining sister chromatids in close proximity.

    “structural maintenance of chromosome (SMC) proteins, including cohesins, are recruited to chromosomes in response to DSBs in budding yeast, where they facilitate DSB repair by HR by maintaining sister chromatids in close proximity (Strom et al. 2004; Unal et al. 2004, 2007; De Piccoli et al. 2006; Lindroos et al. 2006)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Strom et al. 2004

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    • cites Unal et al. 2004, 2007

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    • cites De Piccoli et al. 2006

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    Premisecitation
    § Structural and regulatory functions of DDR foci

    Very few or even a single unrepaired DSB can be sufficient to trigger p53-dependent G1 arrest in human cells or cell death in yeast.

    “very few or even a single unrepaired DSB can be sufficient to trigger p53-dependent G1 arrest in human cells (Huang et al. 1996) or cell death in yeast (Bennett et al. 1993)”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    • cites Bennett et al. 1993

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    Interpretationreasoning
    § Conclusions and future directions

    DNA break-associated proteins and the foci they assemble into are of considerable medical importance, with defects in them being associated with various pathologies, particularly cancer.

    “DNA break-associated proteins and the foci that they assemble into are of considerable medical importance, with defects in them being associated with various pathologies, particularly cancer.”
    Quote in the paperSubstantial claim
66 of 66

  • The paper relies on this without support.

    To ensure efficient signaling and repair of DNA damage, DDR proteins must relocate to the right place at the right time.

    “Toensure the efficient signaling and repair of DNA damage, DDR proteins must relocate to the right place at the right time.”

  • The paper relies on this without support.

    Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR).

    “Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR).”

  • The paper relies on this without support.

    Chromatin acts as a physical barrier to the detection and repair of DNA lesions.

    “Although chromatin acts as a physical barrier to the detection and repair of DNA lesions, it is also a dynamic structure that can be modulated by DNA methylation (Kulis and Esteller 2010), incorporation of histone variants (Bernstein and Hake 2006), histone post-translational modifications (Kouzarides 2007), and nucleosome repositioning by ATP-dependent remodeling complexes (Clapier and Cairns 200”

  • The authors state this as an assumption.

    Focal accumulation of DDR proteins increases their local concentrations, potentiates interactions between them and with damaged DNA, mounts rapid and effective responses to DNA breaks, and makes accidental DDR induction unlikely.

    “It is widely assumed that the focal accumulation of DDR proteins, by increasing their local concentrations, potentiates interactions between them and with the damaged DNA, thus mounting rapid and effective responses to DNA breaks, while at the same time making accidental DDR induction unlikely.”
4 of 4

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Authors
Polo, S. E., & Jackson, S. P.
Affiliations
University of Cambridge (GB)
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2011-03-01
Volume
25
Issue
5
Pages
409-433
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.2021311
PMC
PMC3049283
OpenAlex
W2132396299
Semantic Scholar
b16e0a611825bb8e1aa16542528330fdce091b48
Cited by
1,092
References
373
Citations by year
2026: 25 · 2025: 39 · 2024: 38 · 2023: 45 · 2022: 53 · 2021: 75 · 2020: 55 · 2019: 71 · 2018: 80 · 2017: 83 · 2016: 103 · 2015: 90 · 2014: 107 · 2013: 107 · 2012: 87
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Association pour la Recherche sur le Cancer
  • Wellcome Trust
  • Cancer Research UK (11224, A11224)
  • University of Cambridge
  • European Commission (201630)
  • Biotechnology and Biological Sciences Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
DNA damage response, DNA strand breaks, post-translational modification, spatiotemporal dynamics, genome stability, genotoxic stress
MeSH terms
Animals, DNA Repair, Humans, Mammals, Protein Processing, Post-Translational, Proteins, Saccharomyces, Signal Transduction, DNA Breaks

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