Regulation of DNA‐damage responses and cell‐cycle progression by the chromatin remodelling factor CHD4

“In response to DNA damage, cells initiate a coordinated programme of events, termed the DNA-damage response (DDR), which is critical for maintenance of genome integrity and the prevention of ageing and tumourigenesis (Harper and Elledge, 2007; Jackson and Bartek, 2009).”

“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”

“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”

“Interestingly, proteomic screens in human cells have identified CHD4 as a target for DDR kinases (Matsuoka et al, 2007; Mu et al, 2007; Stokes et al, 2007).”

“It is, therefore, possible that such factors will display synergistic and/or antagonistic functions in the regulation of chromatin compaction at DNA-damage sites, as happens in the context of transcription (Ramirez-Carrozzi et al, 2006; Clapier and Cairns, 2009).”

“In response to DNA damage, cells initiate a coordinated programme of events, termed the DNA-damage response (DDR), which is critical for maintenance of genome integrity and the prevention of ageing and tumourigenesis (Harper and Elledge, 2007; Jackson and Bartek, 2009).”

“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”

“…DNA nicks also activate poly(ADP-ribose) poly- merase (PARP) enzymes that modify target proteins with poly(ADP-ribose) chains (PAR chains) at DNA-damage sites, thereby stimulating the recruitment and/or activity of repair factors (Malanga and Althaus, 2005; Hakme et al, 2008; Rouleau et al, 2010).”

“Furthermore, we found that this CHD4 phosphorylation was prevented when cells were incubated with Wortmannin (Sarkaria et al, 1998) or the ATM inhibitor KU-55933 (Hickson et al, 2004), but not the DNA-PK inhibitor NU-7441 (Leahy et al, 2004) (see Figure 3B; Supplementary Figure S4B).”

“These findings thereby help explain recent observa- tions linking NuRD to cellular ageing (Pegoraro et al, 2009) and might shed light on why patients expressing auto- antibodies against CHD4 display higher cancer incidence (Hill et al, 2001).”

“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”

“To address the biological significance of CHD4 to the DDR, we analysed the effects of its depletion, focusing initially on PARP-mediated repair of DNA breaks (Caldecott, 2008) and ATM-dependent signalling.”

“…complex (nucleosome remodelling deacetylase) that is unique in combining chromatin remodelling activity with histone deacetylase and demethylase functions involved in transcriptional repression (Wade et al, 1998; Xue et al, 1998; Zhang et al, 1998; Denslow and Wade, 2007; Ramirez and Hagman, 2009).”

“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”

“…complex (nucleosome remodelling deacetylase) that is unique in combining chromatin remodelling activity with histone deacetylase and demethylase functions involved in transcriptional repression (Wade et al, 1998; Xue et al, 1998; Zhang et al, 1998; Denslow and Wade, 2007; Ramirez and Hagman, 2009).”

“Cells were analysed 48–72 h after transfection.”

“Interestingly, CHD4 appears to be one of the several, and possibly many, chromatin remodelling factors recruited to DNA breaks in mammalian cells (Murr et al, 2006; Ahel et al, 2009; Gottschalk et al, 2009; Peng et al, 2009; Timinszky et al, 2009).”

“…it is tempting to speculate that this could be through local remo- delling of chromatin to facilitate DNA repair, perhaps in ways similar to those proposed for yeast and other mammalian chromatin remodelling complexes (Park et al, 2006; Ahel et al, 2009; Peng et al, 2009; Sinha et al, 2009).”

“…does not display canonical PAR-binding domains (Karras et al, 2005; Ahel et al, 2008), sequence analyses revealed the presence of putative PAR-binding motifs in the CHD4 amino- and carboxyl-terminal regions that loosely matched a characterized consensus (Pleschke et al, 2000; Gagne et al, 2008).”

“…to full DDR activation (Murga et al, 2007), and accumulating evidence suggests pivotal and direct functions for chromatin remodelling factors in relieving such inhibitory effects (Bao and Shen, 2007; Downs et al, 2007; Osley et al, 2007; Clapier and Cairns, 2009; van Attikum and Gasser, 2009).”

“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”

“…functions for CHD4 and other chromatin remodelling components is also relevant for cancer research in general, given that drugs targeting chromatin-modifying enzymes are being explored as anti- cancer therapies, both for use alone and in combination with DNA-damaging treatments (Ellis et al, 2009).”

“…complex (nucleosome remodelling deacetylase) that is unique in combining chromatin remodelling activity with histone deacetylase and demethylase functions involved in transcriptional repression (Wade et al, 1998; Xue et al, 1998; Zhang et al, 1998; Denslow and Wade, 2007; Ramirez and Hagman, 2009).”

“Localized DNA damage was generated by exposure of cells to a UV-A laser (Limoli and Ward, 1993; Lukas et al, 2003).”

“…does not display canonical PAR-binding domains (Karras et al, 2005; Ahel et al, 2008), sequence analyses revealed the presence of putative PAR-binding motifs in the CHD4 amino- and carboxyl-terminal regions that loosely matched a characterized consensus (Pleschke et al, 2000; Gagne et al, 2008).”

“CHD4 is well characterized as a catalytic subunit of the NuRD transcriptional repressor complex (Wade et al, 1998; Xue et al, 1998; Zhang et al, 1998; Denslow and Wade, 2007; Ramirez and Hagman, 2009).”

“…to full DDR activation (Murga et al, 2007), and accumulating evidence suggests pivotal and direct functions for chromatin remodelling factors in relieving such inhibitory effects (Bao and Shen, 2007; Downs et al, 2007; Osley et al, 2007; Clapier and Cairns, 2009; van Attikum and Gasser, 2009).”

“Furthermore, we found that this CHD4 phosphorylation was prevented when cells were incubated with Wortmannin (Sarkaria et al, 1998) or the ATM inhibitor KU-55933 (Hickson et al, 2004), but not the DNA-PK inhibitor NU-7441 (Leahy et al, 2004) (see Figure 3B; Supplementary Figure S4B).”

“Interestingly, CHD4 appears to be one of the several, and possibly many, chromatin remodelling factors recruited to DNA breaks in mammalian cells (Murr et al, 2006; Ahel et al, 2009; Gottschalk et al, 2009; Peng et al, 2009; Timinszky et al, 2009).”

“Interestingly, CHD4 appears to be one of the several, and possibly many, chromatin remodelling factors recruited to DNA breaks in mammalian cells (Murr et al, 2006; Ahel et al, 2009; Gottschalk et al, 2009; Peng et al, 2009; Timinszky et al, 2009).”

“Notably, CHD4 is a likely target for DDR kinases (Matsuoka et al, 2007; Mu et al, 2007; Stokes et al, 2007), and loss of function of CHD4 or other NuRD components causes accumulation of DNA damage and features of accelerated ageing (Pegoraro et al, 2009).”

“…to full DDR activation (Murga et al, 2007), and accumulating evidence suggests pivotal and direct functions for chromatin remodelling factors in relieving such inhibitory effects (Bao and Shen, 2007; Downs et al, 2007; Osley et al, 2007; Clapier and Cairns, 2009; van Attikum and Gasser, 2009).”

“…it is tempting to speculate that this could be through local remo- delling of chromatin to facilitate DNA repair, perhaps in ways similar to those proposed for yeast and other mammalian chromatin remodelling complexes (Park et al, 2006; Ahel et al, 2009; Peng et al, 2009; Sinha et al, 2009).”

“…DNA nicks also activate poly(ADP-ribose) poly- merase (PARP) enzymes that modify target proteins with poly(ADP-ribose) chains (PAR chains) at DNA-damage sites, thereby stimulating the recruitment and/or activity of repair factors (Malanga and Althaus, 2005; Hakme et al, 2008; Rouleau et al, 2010).”

“Indeed, compacted chromatin can be refractory to full DDR activation (Murga et al, 2007), and accumulating evidence suggests pivotal and direct functions for chromatin remodelling factors in relieving such inhibitory effects (Bao and Shen, 2007; Downs et al, 2007; Osley et al, 2007; Clapier and…”

“This then brings about further chromatin alterations that permit recruitment of additional DDR mediators such as p53-binding protein 1 (53BP1) and breast cancer 1 (BRCA1; Panier and Durocher, 2009).”

“…it is tempting to speculate that this could be through local remo- delling of chromatin to facilitate DNA repair, perhaps in ways similar to those proposed for yeast and other mammalian chromatin remodelling complexes (Park et al, 2006; Ahel et al, 2009; Peng et al, 2009; Sinha et al, 2009).”

“Notably, CHD4 is a likely target for DDR kinases (Matsuoka et al, 2007; Mu et al, 2007; Stokes et al, 2007), and loss of function of CHD4 or other NuRD components causes accumulation of DNA damage and features of accelerated ageing (Pegoraro et al, 2009).”

“…DNA nicks also activate poly(ADP-ribose) poly- merase (PARP) enzymes that modify target proteins with poly(ADP-ribose) chains (PAR chains) at DNA-damage sites, thereby stimulating the recruitment and/or activity of repair factors (Malanga and Althaus, 2005; Hakme et al, 2008; Rouleau et al, 2010).”

“…to full DDR activation (Murga et al, 2007), and accumulating evidence suggests pivotal and direct functions for chromatin remodelling factors in relieving such inhibitory effects (Bao and Shen, 2007; Downs et al, 2007; Osley et al, 2007; Clapier and Cairns, 2009; van Attikum and Gasser, 2009).”

“Localized DNA damage was generated by exposure of cells to a UV-A laser (Limoli and Ward, 1993; Lukas et al, 2003).”

“…to full DDR activation (Murga et al, 2007), and accumulating evidence suggests pivotal and direct functions for chromatin remodelling factors in relieving such inhibitory effects (Bao and Shen, 2007; Downs et al, 2007; Osley et al, 2007; Clapier and Cairns, 2009; van Attikum and Gasser, 2009).”

“…complex (nucleosome remodelling deacetylase) that is unique in combining chromatin remodelling activity with histone deacetylase and demethylase functions involved in transcriptional repression (Wade et al, 1998; Xue et al, 1998; Zhang et al, 1998; Denslow and Wade, 2007; Ramirez and Hagman, 2009).”

“…it is tempting to speculate that this could be through local remo- delling of chromatin to facilitate DNA repair, perhaps in ways similar to those proposed for yeast and other mammalian chromatin remodelling complexes (Park et al, 2006; Ahel et al, 2009; Peng et al, 2009; Sinha et al, 2009).”

“Consistent with this, we found that depletion of the p300 acetyltransferase, which is responsible for p53 Lys-382 acetylation (Carter and Vousden, 2009; Kruse and Gu, 2009), reduced both p53 acetylation and p21 levels, and moreover, rescued cell-cycle progression in CHD4-depleted cells (Figure 6F and G), supporting th…”

“…22, 2010 ª2010 Elsevier Inc. 181 182 Molecular Cell 40, October 22, 2010 ª2010 Elsevier Inc. recruitment of DNA repair and chromatin modifying complexes, such as polycomb and histone deacetylase (HDAC) complexes, at DNA damage sites (Polo et al., 2010; Schreiber et al., 2006; Chou et al., 2010).”

“PARylation at DNA breaks is also required for accrual of the chromatin remodeling factors ALC1 and CHD4 (Ahel et al. 2009; Gottschalk et al. 2009; Chou et al. 2010; Polo et al. 2010), the Polycomb histone-modifying complex (Chou et al. 2010), and the histone variant macroH2A (Timinszky et al. 2009).”