Requirement of ATM-Dependent Monoubiquitylation of Histone H2B for Timely Repair of DNA Double-Strand Breaks

Moyal, Lilach; Lerenthal, Yaniv; Gana‐Weisz, Mali; Mass, Gilad; So, Sairei; Wang, Shih-Ya; Eppink, Berina; Chung, Young-Min; Shalev, Gil; Shema, Efrat; Shkedy, Dganit; Smorodinsky, Nechama I.; Vliet, Nicole van; Küster, Bernhard; Mann, Matthias; Ciechanover, Aaron; Dahm-Daphi, Jochen; Kanaar, Roland; Hu, Mickey C.T.; Chen, David J.; Oren, Moshe; Shiloh, Yosef

doi:10.1016/j.molcel.2011.03.009

Cited by 55 publications

(117 citation statements)

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“…Intriguingly, we found that the levels of H2Bub1 are strikingly decreased after erastin treatment, suggesting that H2Bub1 may be involved in the regulation of ferroptosis ( Fig 1A). In addition to knockdown of RNF20 expression, we and others previously indicated that overexpression of the K120R mutant of H2B (H2BK120R) can also downregulate the levels of endogenous H2Bub1 making a useful way to examine the roles of H2Bub1 [44,45]. In addition to knockdown of RNF20 expression, we and others previously indicated that overexpression of the K120R mutant of H2B (H2BK120R) can also downregulate the levels of endogenous H2Bub1 making a useful way to examine the roles of H2Bub1 [44,45].…”

Section: Loss Of H2bub1 Significantly Sensitizes Cells To Erastin-indmentioning

confidence: 99%

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Wang

Zhang³

et al. 2019

EMBO Reports

158

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Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non‐apoptotic cell death characterized by the iron‐dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin‐induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1‐mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.

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Section: Loss Of H2bub1 Significantly Sensitizes Cells To Erastin-indmentioning

confidence: 99%

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Wang

Zhang³

et al. 2019

EMBO Reports

158

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“…In addition to H2A ubiquitylation, also H2B ubiquitylation (at K120) was recently recognized to play a role in the DDR (Moyal et al., 2011; Nakamura et al., 2011). During transcription, H2B ubiquitylation (uH2B) is carried out by the RNF20/RNF40 complex (Pavri et al., 2006).…”

Section: Histone Modificationsmentioning

confidence: 99%

“…During transcription, H2B ubiquitylation (uH2B) is carried out by the RNF20/RNF40 complex (Pavri et al., 2006). Likewise, RNF20/40‐induced uH2B is directly involved in the DDR and promotes DNA repair by both HR and NHEJ (Moyal et al., 2011; Nakamura et al., 2011). RNF20/40 is directly recruited to DSBs and damage‐induced uH2B requires ATM‐mediated phosphorylation of RNF20/40 (Moyal et al., 2011).…”

Section: Histone Modificationsmentioning

confidence: 99%

“…RNF20/40 is directly recruited to DSBs and damage‐induced uH2B requires ATM‐mediated phosphorylation of RNF20/40 (Moyal et al., 2011). The recruitment mechanism of RNF20/40 to DSBs remains to be established as recruitment required neither ATM nor NBS1 (Moyal et al., 2011; Nakamura et al., 2011). At present, it seems that the MDC1–RNF8–uH2A pathway is not affected by, nor does it affect, the RNF20/40–uH2B pathway, suggesting that ATM‐dependent uH2A and uH2B pathways may be mechanistically distinct.…”

Section: Histone Modificationsmentioning

confidence: 99%

“…Significant crosstalk has been reported between uH2B and histone methylation at H3K4 and H3K79 during transcription (Kim et al., 2009b). While one study reported no difference in H3K4me or K79me following DNA damage (Moyal et al., 2011), another study reported elevated H3K4me at DSBs (Nakamura et al., 2011). Depletion of RNF20 triggers transformation and tumorigenesis in cultured cells, and cancers were found to often have decreased levels of RNF20, identifying this gene as a potential tumor suppressor.…”

Section: Histone Modificationsmentioning

confidence: 99%

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Chromatin and the DNA damage response: The cancer connection

2011

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Cancer DNA damage response A B S T R A C TThe integrity of the human genome is constantly threatened by genotoxic agents that cause DNA damage. Inefficient or inaccurate repair of DNA lesions triggers genome instability and can lead to cancer development or even cell death. Cells counteract the adverse effects of DNA lesions by activating the DNA damage response (DDR), which entails a coordinated series of events that regulates cell cycle progression and repair of DNA lesions. Efficient DNA repair in living cells is complicated by the packaging of genomic DNA into a condensed, often inaccessible structure called chromatin. Cells utilize post-translational histone modifications and ATP-dependent chromatin remodeling to modulate chromatin structure and increase the accessibility of the repair machinery to lesions embedded in chromatin. Here we review and discuss our current knowledge and recent advances on DNA damage-induced chromatin changes and their implications for the mammalian DNA damage response, genome stability and carcinogenesis. Exploiting our improving understanding of how modulators of chromatin structure orchestrate the DDR may provide new avenues to improve cancer management.ª 2011 Federation of European Biochemical Societies.Published by Elsevier B.V. All rights reserved. IntroductionMaintaining genomic stability is of vital importance to protect cells against the harmful consequences of DNA damage, which, if not properly dealt with, can lead to genomic instabilty, cancer or cell death (Negrini et al., 2010;Jackson and Bartek, 2009). Exposure to solar ultra-violet (UV) light triggers the formation of tens of thousands of DNA lesions per cell per hour in the form of DNA intra-strand cross-links in genomic DNA (Jackson and Bartek, 2009). These lesions are either cytotoxic and can trigger cell death or accelerated ageing, or they are mutagenic and can lead to the onset of skin cancer (Mitchell et al., 2003). Genomic integrity is also threatened by the formation of chromosomal double-strand DNA breaks (DSBs), which arise after exposure of cells to ionizing radiation or chemotherapeutical agents, or through the collapse of replication forks when replication blocks at DNA intra-strand cross-links induced by solar UV light (Hoeijmakers, 2001). To protect against the adverse effects of these DNA lesions, cells activate a coordinated series of events that regulate cell cycle progression and repair of these lesions (Hoeijmakers, 2001;Polo and Jackson, 2011;Bekker-Jensen and Mailand, 2011;Ciccia and Elledge, 2010). This cellular response to DNA damage is highly relevant to counteract tumor development, which is underscored by the fact that several cancer-prone human disorders, including Xeroderma pigmentosum, Nijmegen

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The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B

et al. 2019

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Chronic infection of hepatitis B virus (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein, hepatitis B x protein (HBx), that is crucial for viral replication and interferes with multiple cellular activities including gene expression, histone modifications, and genomic stability. To date, it remains unclear how disruption of these activities contributes to hepatocarcinogenesis. Here, we report that HBV exhibits antiresection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This antiresection activity occurs in primary human hepatocytes undergoing a natural viral infection–replication cycle as well as in cells with integrated HBV genomes. Among the seven HBV‐encoded proteins, we identified HBx as the sole viral factor that inhibits resection. By disrupting an evolutionarily conserved Cullin4A–damage‐specific DNA binding protein 1–RING type of E3 ligase, CRL4 WDR70 , through its H‐box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 at double‐strand breaks, thus reducing the efficiency of long‐range resection. We further show that directly impairing H2B monoubiquitylation elicited tumorigenesis upon engraftment of deficient cells in athymic mice, confirming that the impairment of CRL4 WDR70 function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrate that lack of H2B monoubiquitylation is manifest in human HBV‐associated HCC when compared with HBV‐free HCC, implying corresponding defects of epigenetic regulation and end resection. Conclusion: The antiresection activity of HBx induces an HR defect and genomic instability and contributes to tumorigenesis of host hepatocytes.

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Requirement of ATM-Dependent Monoubiquitylation of Histone H2B for Timely Repair of DNA Double-Strand Breaks

Cited by 55 publications

References 0 publications

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Chromatin and the DNA damage response: The cancer connection

The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B

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