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ATM-Dependent Chromatin Changes Silence Transcription In cis to DNA Double-Strand Breaks
Open accessAbstract
DNA double-strand breaks (DSBs) initiate extensive local and global alterations in chromatin structure, many of which depend on the ATM kinase. Histone H2A ubiquitylation (uH2A) on chromatin surrounding DSBs is one example, thought to be important for recruitment of repair proteins. uH2A is also implicated in transcriptional repression; an intriguing yet untested hypothesis is that this function is conserved in the context of DSBs. Using a novel reporter that allows for visualization of repair protein recruitment and local transcription in single cells, we describe an ATM-dependent transcriptional silencing program in cis to DSBs. ATM prevents RNA polymerase II elongation-dependent chromatin decondensation at regions distal to DSBs. Silencing is partially dependent on E3 ubiquitin ligases RNF8 and RNF168, whereas reversal of silencing relies on the uH2A deubiquitylating enzyme USP16. These findings give insight into the role of posttranslational modifications in mediating crosstalk between diverse processes occurring on chromatin.
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“DSBs were previously shown to interfere with the expression of break-proximal genes in tumor cell lines (11–13,42).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [13]
In the citing paper
“Consistent with this, recent findings demonstrate transcriptional repression in cis to DSBs, which depends on DNA damage signaling and ceases after DSB repair is complete (10–13).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [13]
In the citing paper
“This work is, however, limited to highly proliferative tumor cell lines, and its implications for animal tissues, which often exhibit little or no proliferation, remain unclear.”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [13]
In the citing paper
“DSBs are known to promote a dynamic reorganization of break-proximal chromatin, with the potential to affect the expression of both break-proximal and ostensibly undamaged genes (10,13,19,45,48–50).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [13]
In the citing paper
“our findings, thus, suggest that most tissues have the potential to restore DSB-induced gene deregulation, although the kinetics of DSB repair and DNA damage-associated gene silencing may differ depending on cell type and/or cell cycle state.”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [13]
In the citing paper
“The latter is in agreement with several reports implicating the DDR mediators ATM and DNA-PK in DSB-proximal repressive chromatin formation as well as transcriptional silencing (9–13,50).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [13]
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Metadata
- Authors
- Shanbhag, N. M., Rafalska-Metcalf, I. U., Balane-Bolivar, C., Janicki, S. M., & Greenberg, R. A.
- Affiliations
- Abramson Cancer Center (US)
- The Wistar Institute (US)
- Corresponding author
- Greenberg, Roger A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 141
- Issue
- 6
- Pages
- 970-981
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2920610
- OpenAlex
- W2135144687
- Cited by
- 737
- References
- 53
- Citations by year
- 2026: 30 · 2025: 28 · 2024: 45 · 2023: 45 · 2022: 49 · 2021: 71 · 2020: 51 · 2019: 45 · 2018: 38 · 2017: 49 · 2016: 45 · 2015: 44 · 2014: 46 · 2013: 54 · 2012: 42
- FWCI
- 19.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1142 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Genentech
- National Cancer Institute (K08CA106597, T32CA115299, R01CA138835, 1-T32-CA-115299-01A2)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- ATM kinase, DNA double-strand breaks, transcriptional silencing, chromatin decondensation, RNA polymerase II elongation, RNF8, RNF168, USP16, E3 ubiquitin ligase, post-translational modification
- MeSH terms
- Chromatin, DNA Damage, DNA-Binding Proteins, Histones, Humans, Transcription, Genetic, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Gene Silencing, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Cell Line, Tumor, DNA Breaks, Double-Stranded, Ubiquitination, Ataxia Telangiectasia Mutated Proteins
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