A phosphorylation-and-ubiquitylation circuitry driving ATR activation and homologous recombination

Dubois, Jacques; Yates, Maïlyn; Gaudreau-Lapierre, Antoine; Clément, Geneviève; Cappadocia, Laurent; Gaudreau, Luc; Zou, Lee; Maréchal, Alexandre

doi:10.1093/nar/gkx571

Cited by 39 publications

(55 citation statements)

References 78 publications

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“…S2 F). These results are in keeping with a prior report using a similar RPA mutant in WT cells (Dubois et al, 2017). Interestingly, we see an increase in RPA ubiquitination of the RPA D mutant in BRCA2-depleted cells relative to control cells ( Fig.…”

Section: Duan Et Alsupporting

confidence: 93%

E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells

Duan

Mansour

Reed

et al. 2020

Journal of Cell Biology

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BRCA1/2 help maintain genomic integrity by stabilizing stalled forks. Here, we identify the E3 ligase RFWD3 as an essential modulator of stalled fork stability in BRCA2-deficient cells and show that codepletion of RFWD3 rescues fork degradation, collapse, and cell sensitivity upon replication stress. Stalled forks in BRCA2-deficient cells accumulate phosphorylated and ubiquitinated replication protein A (ubq-pRPA), the latter of which is mediated by RFWD3. Generation of this intermediate requires SMARCAL1, suggesting that it depends on stalled fork reversal. We show that in BRCA2-deficient cells, rescuing fork degradation might not be sufficient to ensure fork repair. Depleting MRE11 in BRCA2-deficient cells does block fork degradation, but it does not prevent fork collapse and cell sensitivity in the presence of replication stress. No such ubq-pRPA intermediate is formed in BRCA1-deficient cells, and our results suggest that BRCA1 may function upstream of BRCA2 in the stalled fork repair pathway. Collectively, our data uncover a novel mechanism by which RFWD3 destabilizes forks in BRCA2-deficient cells.

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Section: Duan Et Alsupporting

confidence: 93%

E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells

Duan

Mansour

Reed

et al. 2020

Journal of Cell Biology

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“…6C,D). As ATR activation in vitro requires the expression of both PRP19 (31,32) and BRUCE (Fig. 4), an overall reduction of PRP19 levels in LKO was also observed (Fig.…”

Section: Bruce Promotes the Atr Ddr Signaling During Repair Of Den-inmentioning

confidence: 79%

“…PRP19 has been shown to regulate DNA repair . Specifically, PRP19’s E3 ligase activity catalyzes the nondegradative ubiquitination of RPA, thereby promoting RPA‐Ub‐mediated ATR activation . Additionally, PRP19 is implicated in cellular resistance to DNA ICLs and the protection of replication forks during the replication stress response .…”

Section: Resultsmentioning

confidence: 99%

“…(29,30) Specifically, PRP19's E3 ligase activity catalyzes the nondegradative ubiquitination of RPA, thereby promoting RPA-Ub-mediated ATR activation. (31,32) Additionally, PRP19 is implicated in cellular resistance to DNA ICLs and the protection of replication forks during the replication stress response. (30) However, it remains unclear whether PRP19 functions at the earlier steps of FANCD2 mono-ubiquitination and its foci formation or during later steps.…”

Section: Bruce Acts As a Scaffold That Interacts With Prp19/prpf19 mentioning

confidence: 99%

“…Studies show that PRP19 mediates ATR activation by promoting nondegradative ubiquitination of RPA. (31,32) Considering that BRUCE is a ubiquitin conjugase and is required for RPA foci formation (Fig. 1D), we examined whether BRUCE facilitates RPA ubiquitination to promote ATR signaling.…”

Section: Bruce Acts As a Scaffold That Interacts With Prp19/prpf19 mentioning

confidence: 99%

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The BRUCE‐ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development

et al. 2019

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Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR (ataxia‐telangiectasia mutated [ATM] and RAD3‐related) is a master regulatory kinase that activates the replication stress response to overcome replication barriers. Although many downstream effectors of ATR have been established, the upstream regulators of ATR and the effect of such regulation on liver cancer remain unclear. The ubiquitin conjugase BRUCE (BIR Repeat containing Ubiquitin‐Conjugating Enzyme) is a guardian of chromosome integrity and activator of ATM signaling, which promotes DNA double‐strand break repair through homologous recombination. Here we demonstrate the functions for BRUCE in ATR activation in vitro and liver tumor suppression in vivo. BRUCE is recruited to induced DNA damage sites. Depletion of BRUCE inhibited multiple ATR‐dependent signaling events during replication stress, including activation of ATR itself, phosphorylation of its downstream targets CHK1 and RPA, and the mono‐ubiquitination of FANCD2. Consequently, BRUCE deficiency resulted in stalled DNA replication forks and increased firing of new replication origins. The in vivo impact of BRUCE loss on liver tumorigenesis was determined using the hepatocellular carcinoma model induced by genotoxin diethylnitrosamine. Liver‐specific knockout of murine Bruce impaired ATR activation and exacerbated inflammation, fibrosis and hepatocellular carcinoma, which exhibited a trabecular architecture, closely resembling human hepatocellular carcinoma (HCC). In humans, the clinical relevance of BRUCE down‐regulation in liver disease was found in hepatitis, cirrhosis, and HCC specimens, and deleterious somatic mutations of the Bruce gene was found in human hepatocellular carcinoma in the Cancer Genome Atlas database. Conclusion: These findings establish a BRUCE‐ATR signaling axis in accurate DNA replication and suppression of liver cancer in mice and humans and provides a clinically relevant HCC mouse model.

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Cell-Autonomous (Cell-Intrinsic) Stress Responses

Land

2018

Damage-Associated Molecular Patterns in Human Diseases

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A phosphorylation-and-ubiquitylation circuitry driving ATR activation and homologous recombination

Cited by 39 publications

References 78 publications

E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells

E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells

The BRUCE‐ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development

Cell-Autonomous (Cell-Intrinsic) Stress Responses

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