Global Regulation of H2A.Z Localization by the INO80 Chromatin-Remodeling Enzyme Is Essential for Genome Integrity

Papamichos‐Chronakis, Manolis; Watanabe, Shinya; Rando, Oliver J.; Peterson, Craig L.

doi:10.1016/j.cell.2010.12.021

Cited by 364 publications

(353 citation statements)

References 55 publications

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“…Inactivation of NuA4-Tip60 blocks both H2A.Z exchange and H4 acetylation, leading to a reduction in chromatin mobility at DSBs. Consequently, loss of H2A.Z exchange leads to defective DSB repair, increased sensitivity to DNA damage, and genomic instability (13,18,19).…”

mentioning

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.

118

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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mentioning

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.

118

155

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“…A study has suggested that INO80 functions in normal DNA replication in human cells 10 . Consistent with its role in various chromosomal processes, INO80 is critical for the maintenance of genome stability [10][11][12][13] .…”

mentioning

confidence: 94%

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

Lee

Lee²,

Hur³

et al. 2014

Nat Commun

103

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The INO80 chromatin-remodelling complex has been implicated in DNA replication during stress in yeast. However, its role in normal DNA replication and its underlying mechanisms remain unclear. Here, we show that INO80 binds to replication forks and promotes fork progression in human cells under unperturbed, normal conditions. We find that Ino80, which encodes the catalytic ATPase of INO80, is essential for mouse embryonic DNA replication and development. Ino80 is recruited to replication forks through interaction with ubiquitinated H2A-aided by BRCA1-associated protein-1 (BAP1), a tumour suppressor and nuclear de-ubiquitinating enzyme that also functions to stabilize Ino80. Importantly, Ino80 is downregulated in BAP1-defective cancer cells due to the lack of an Ino80 stabilization mechanism via BAP1. Our results establish a role for INO80 in normal DNA replication and uncover a mechanism by which this remodeler is targeted to replication forks, suggesting a molecular basis for the tumour-suppressing function of BAP1.

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“…In addition to its role in the repair of DSBs, yINO80 is required to maintain genome stability by modulating histone H2A.Z distribution in the genome [47] and to promote proper chromosome segregation [48]. We therefore hypothesized that deletion of mIno80 results in genomic instability, a potentially tumor-promoting event.…”

Section: Reduced Transformation Potential Of Mino80-null Cellsmentioning

confidence: 99%

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

et al. 2013

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The INO80 (inositol requiring mutant 80) chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mIno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mIno80. Deletion of mIno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mIno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of γ-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response. mIno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair (HDR) at telomeres. Fragile telomeres were prominent in mIno80 ∆/∆ MEFs, suggesting that chromatin remodeling is required for efficient telomere replication. mIno80 −/− mouse embryos die early during embryogenesis, while conditional deletion of mIno80 in adult mice results in weight loss and premature death. In a p53 −/− tumorprone background, mIno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dysfunctional telomeres, and maintenance of genome stability.

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Global Regulation of H2A.Z Localization by the INO80 Chromatin-Remodeling Enzyme Is Essential for Genome Integrity

Cited by 364 publications

References 55 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

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

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