Heterochromatin protein 1 is recruited to various types of DNA damage

Luijsterburg, Martijn S.; Dinant, Christoffel; Lans, Hannes; Stap, Jan; Wiernasz, Elżbieta; Lagerwerf, Saskia; Warmerdam, Daniël O.; Lindh, Michael; Brink, Maartje C.; Dobrucki, Jurek; Aten, Jacob A.; Fousteri, Maria; Jansen, Gert; Dantuma, Nico P.; Vermeulen, Wim; Mullenders, Leon H.F.; Houtsmuller, Adriaan B.; Verschure, Pernette J.; Driel, Roel van

doi:10.1083/jcb.200810035

Cited by 235 publications

(288 citation statements)

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“…Further, we showed H2A.Z retention at DSBs blocked the shift to open chromatin, indicating that the initial exchange of H2A.Z stabilizes chromatin immediately after DNA damage. Other repressive factors, including HP1 and NuRD (10,(40)(41)(42), are also rapidly, but transiently recruited to DSBs. Transient loading of H2A.Z and other repressors may therefore temporarily "heterochromatinize" nucleosomes at breaks, stabilizing the damaged chromatin, and allowing the cell time to process the chromatin for DNA repair (Fig.…”

Section: Discussionmentioning

confidence: 99%

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

Gürsoy-Yüzügüllü

Ayrapetov

Price

2015

Proc. Natl. Acad. Sci. U.S.A.

121

155

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The repair of DNA double-strand breaks (DSBs) requires open, flexible chromatin domains. The NuA4–Tip60 complex creates these flexible chromatin structures by exchanging histone H2A.Z onto nucleosomes and promoting acetylation of histone H4. Here, we demonstrate that the accumulation of H2A.Z on nucleosomes at DSBs is transient, and that rapid eviction of H2A.Z is required for DSB repair. Anp32e, an H2A.Z chaperone that interacts with the C-terminal docking domain of H2A.Z, is rapidly recruited to DSBs. Anp32e functions to remove H2A.Z from nucleosomes, so that H2A.Z levels return to basal within 10 min of DNA damage. Further, H2A.Z removal by Anp32e disrupts inhibitory interactions between the histone H4 tail and the nucleosome surface, facilitating increased acetylation of histone H4 following DNA damage. When H2A.Z removal by Anp32e is blocked, nucleosomes at DSBs retain elevated levels of H2A.Z, and assume a more stable, hypoacetylated conformation. Further, loss of Anp32e leads to increased CtIP-dependent end resection, accumulation of single-stranded DNA, and an increase in repair by the alternative nonhomologous end joining pathway. Exchange of H2A.Z onto the chromatin and subsequent rapid removal by Anp32e are therefore critical for creating open, acetylated nucleosome structures and for controlling end resection by CtIP. Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair.

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Section: Discussionmentioning

confidence: 99%

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

Gürsoy-Yüzügüllü

Ayrapetov

Price

2015

Proc. Natl. Acad. Sci. U.S.A.

121

155

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“…Previous work demonstrated that the repressive HP1 and kap-1 proteins were also recruited to DSBs (4,22,23,32,36), although how these proteins contributed to DSB repair was not clear. Kap-1, HP1 family members, and suv39h1 can form large repressive complexes (24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

“…Two heterochromatin-binding proteins, kap-1 and HP1, are corecruited to sites of DNA damage (22,23), although how they impact DSB repair is not clear. However, suv39h1 can interact with kap-1/HP1 repressor complexes (20,21,24), suggesting that kap-1 and HP1 may recruit suv39h1 to DSBs.…”

Section: Resultsmentioning

confidence: 99%

DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

Ayrapetov

Gürsoy-Yüzügüllü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

319

335

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Dynamic changes in histone modification are critical for regulating DNA double-strand break (DSB) repair. Activation of the Tip60 acetyltransferase by DSBs requires interaction of Tip60 with histone H3 methylated on lysine 9 (H3K9me3). However, how H3K9 methylation is regulated during DSB repair is not known. Here, we demonstrate that a complex containing kap-1, HP1, and the H3K9 methyltransferase suv39h1 is rapidly loaded onto the chromatin at DSBs. Suv39h1 methylates H3K9, facilitating loading of additional kap-1/HP1/suv39h1 through binding of HP1's chromodomain to the nascent H3K9me3. This process initiates cycles of kap-1/HP1/ suv39h1 loading and H3K9 methylation that facilitate spreading of H3K9me3 and kap-1/HP1/suv39h1 complexes for tens of kilobases away from the DSB. These domains of H3K9me3 function to activate the Tip60 acetyltransferase, allowing Tip60 to acetylate both ataxia telangiectasia-mutated (ATM) kinase and histone H4. Consequently, cells lacking suv39h1 display defective activation of Tip60 and ATM, decreased DSB repair, and increased radiosensitivity. Importantly, activated ATM rapidly phosphorylates kap-1, leading to release of the repressive kap-1/HP1/suv39h1 complex from the chromatin. ATM activation therefore functions as a negative feedback loop to remove repressive suv39h1 complexes at DSBs, which may limit DSB repair. Recruitment of kap-1/HP1/suv39h1 to DSBs therefore provides a mechanism for transiently increasing the levels of H3K9me3 in open chromatin domains that lack H3K9me3 and thereby promoting efficient activation of Tip60 and ATM in these regions. Further, transient formation of repressive chromatin may be critical for stabilizing the damaged chromatin and for remodeling the chromatin to create an efficient template for the DNA repair machinery.histone methylation | homologous recombination D NA double-strand breaks (DSBs) are toxic and must be repaired to maintain genomic stability. Detection of DSBs requires recruitment of the mre11-rad50-nbs1 (MRN) complex to the DNA ends (1). MRN then recruits and activates the ataxia telangiectasia-mutated (ATM) kinase (2, 3) through a mechanism that also requires the Tip60 acetyltransferase (3). Tip60 directly acetylates and activates ATM's kinase activity (4-6) and functions, in combination with MRN, to promote ATM-dependent phosphorylation of DSB repair proteins (3), including histone H2AX. This process creates domains of phosphorylated H2AX (γH2AX) extending for hundreds of kilobases along the chromatin (7,8). Mdc1 then binds to γH2AX, providing a landing pad for other DSB repair proteins, including the RNF8/RNF168 ubiquitin ligases (1, 3, 9, 10). Tip60 also plays a critical role in regulating chromatin structure at DSBs as part of the NuA4-Tip60 complex (11). NuA4-Tip60 catalyzes histone exchange (via the p400 ATPase subunit) and acetylation of histone H4 (by Tip60) at DSBs (12-15), leading to the formation of open, flexible chromatin domains adjacent to the break (12, 13). These open chromatin structures then facilitate histone ub...

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“…2 Following UV irradiation, exposure to α particles, soft X-rays and laser micro-irradiation, mammalian HP1 paralogs show reproducible accumulation at sites of damage. [14][15][16][17] While the mechanism of recruitment to sites of DNA damage for all HP1 paralogs involves their direct interaction with the largest subunit of the chromatin assembly factor 1 (CAF-1), 17 several lines of evidence indicate that their roles might not completely overlap. In mammalian cells, HP1α knockdown impairs the recruitment of the homologous recombination protein RAD51 to sites of local damage as well as cell survival after ionizing radiation.…”

Section: Introductionmentioning

confidence: 99%

Differential contribution of HP1 proteins to DNA end resection and homology-directed repair

Soria

Almouzni

2013

Cell Cycle

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Heterochromatin protein 1 is recruited to various types of DNA damage

Cited by 235 publications

References 50 publications

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

Differential contribution of HP1 proteins to DNA end resection and homology-directed repair

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