Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase

Schmid, Jonas; Berti, Matteo; Walser, Franziska; Raso, Maria Chiara; Schmid, F; Krietsch, Jana; Stoy, Henriette; Zwicky, Katharina; Ursich, Sebastian; Freire, Raimundo; Lopes, Massimo; Penengo, Lorenza

doi:10.1016/j.molcel.2018.07.011

Cited by 92 publications

(92 citation statements)

References 47 publications

(76 reference statements)

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“…that have been described as cellular replication factories in unperturbed conditions (Fig. 5A) (49). Thus, these results support a model in which E7 interacts with a subpopulation of RNF168 that localizes at replication forks.…”

Section: Rnf168 Interacts With E7 From Hr-hpvs and Is Required For Viralsupporting

confidence: 84%

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Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response

Sitz

Blanchet

Gameiro

et al. 2019

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

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High-risk human papillomaviruses (HR-HPVs) promote cervical cancer as well as a subset of anogenital and head and neck cancers. Due to their limited coding capacity, HPVs hijack the host cell’s DNA replication and repair machineries to replicate their own genomes. How this host–pathogen interaction contributes to genomic instability is unknown. Here, we report that HPV-infected cancer cells express high levels of RNF168, an E3 ubiquitin ligase that is critical for proper DNA repair following DNA double-strand breaks, and accumulate high numbers of 53BP1 nuclear bodies, a marker of genomic instability induced by replication stress. We describe a mechanism by which HPV E7 subverts the function of RNF168 at DNA double-strand breaks, providing a rationale for increased homology-directed recombination in E6/E7-expressing cervical cancer cells. By targeting a new regulatory domain of RNF168, E7 binds directly to the E3 ligase without affecting its enzymatic activity. As RNF168 knockdown impairs viral genome amplification in differentiated keratinocytes, we propose that E7 hijacks the E3 ligase to promote the viral replicative cycle. This study reveals a mechanism by which tumor viruses reshape the cellular response to DNA damage by manipulating RNF168-dependent ubiquitin signaling. Importantly, our findings reveal a pathway by which HPV may promote the genomic instability that drives oncogenesis.

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Section: Rnf168 Interacts With E7 From Hr-hpvs and Is Required For Viralsupporting

confidence: 84%

“…RNF168 was reported to promote efficient DNA replication by stabilizing replication forks in S phase (49). Thus, E7 may redirect this E3 ligase to viral replication centers to promote the replication of its own genome (model 1).…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response

Sitz

Blanchet

Gameiro

et al. 2019

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

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“…However, it is also possible that intermediates of ICL processing ahead or behind replication forks contribute to boost ATR activation and phosphorylation of the relevant targets. Interestingly, fork reversal observed in unperturbed cells—likely occurring at endogenous difficult-to-replicate regions—is uncoupled from globally detectable ATR signaling and H2AX phosphorylation ( Figure 7 H) ( Schmid et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links

et al. 2018

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SummaryInterstrand cross-links (ICLs) are toxic DNA lesions interfering with DNA metabolism that are induced by widely used anticancer drugs. They have long been considered absolute roadblocks for replication forks, implicating complex DNA repair processes at stalled or converging replication forks. Recent evidence challenged this view, proposing that single forks traverse ICLs by yet elusive mechanisms. Combining ICL immunolabeling and single-molecule approaches in human cells, we now show that ICL induction leads to global replication fork slowing, involving forks not directly challenged by ICLs. Active fork slowing is linked to rapid recruitment of RAD51 to replicating chromatin and to RAD51/ZRANB3-mediated fork reversal. This global modulation of fork speed and architecture requires ATR activation, promotes single-fork ICL traverse—here, directly visualized by electron microscopy—and prevents chromosomal breakage by untimely ICL processing. We propose that global fork slowing by remodeling provides more time for template repair and promotes bypass of residual lesions, limiting fork-associated processing.

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“…RNF2 and BAP1 as well as ubiquitinated H2A were also found associated with replication forks by isolation of proteins on nascent DNA (iPOND) (21). Interestingly, the ubiquitination of H2A by RNF168 (at K13/15) was recently reported to govern DNA replication as well (30). It is thus tempting to speculate that both the addition and the removal of ubiquitin to and from H2A, each at specific stages of DNA synthesis and histone incorporation, coordinate the synthesis of DNA with the concomitant duplication of chromatin structures.…”

Section: Discussionmentioning

confidence: 99%

Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication

Ina

Wohlberedt

Magerhans

et al. 2018

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

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The p53–Mdm2 system is key to tumor suppression. We have recently reported that p53 as well as Mdm2 are capable of supporting DNA replication fork progression. On the other hand, we found that Mdm2 is a modifier of chromatin, modulating polycomb repressor complex (PRC)-driven histone modifications. Here we show that, similar to Mdm2 knockdown, the depletion of PRC members impairs DNA synthesis, as determined in fiber assays. In particular, the ubiquitin ligase and PRC1 component RNF2/Ring1B is required to support DNA replication, similar to Mdm2. Moreover, the Ring finger domain of Mdm2 is not only essential for its ubiquitin ligase activity, but also for proper DNA replication. Strikingly, Mdm2 overexpression can rescue RNF2 depletion with regard to DNA replication fork progression, and vice versa, strongly suggesting that the two ubiquitin ligases perform overlapping functions in this context. H2A overexpression also rescues fork progression upon depletion of Mdm2 or RNF2, but only when the ubiquitination sites K118/K119 are present. Depleting the H2A deubiquitinating enzyme BAP1 reduces the fork rate, suggesting that both ubiquitination and deubiquitination of H2A are required to support fork progression. The depletion of Mdm2 elicits the accumulation of RNA/DNA hybrids, suggesting R-loop formation as a mechanism of impaired DNA replication. Accordingly, RNase H overexpression or the inhibition of the transcription elongation kinase CDK9 each rescues DNA replication upon depletion of Mdm2 or RNF2. Taken together, our results suggest that chromatin modification by Mdm2 and PRC1 ensures smooth DNA replication through the avoidance of R-loop formation.

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Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase

Cited by 92 publications

References 47 publications

Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response

Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response

ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links

Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication

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