E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells
| Autor: | Ben Liu, Benjamin Parent, Sarah Mansour, Zsofia Sztupinszki, Haohui Duan, Andrew E. H. Elia, Judy Garber, Rachel Reed, Zoltan Szallasi, Nicolai Juul Birkbak, Shailja Pathania, Margaret K Gillis |
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| Rok vydání: | 2020 |
| Předmět: |
DNA Replication
0301 basic medicine DNA Repair endocrine system diseases Cell Survival Ubiquitin-Protein Ligases Article Fork (software development) DNA biology 03 medical and health sciences 0302 clinical medicine Ubiquitin Cell Line Tumor Replication Protein A Humans Hydroxyurea Phosphorylation RNA Small Interfering skin and connective tissue diseases Replication protein A Cancer BRCA2 Protein Cell sensitivity MRE11 Homologue Protein biology Replication stress BRCA1 Protein Cell Cycle DNA Helicases Ubiquitination Cell Biology Ubiquitin ligase Cell biology enzymes and coenzymes (carbohydrates) 030104 developmental biology 030220 oncology & carcinogenesis Mutation biology.protein Rad51 Recombinase DNA Damage |
| Zdroj: | The Journal of Cell Biology Duan, H, Mansour, S, Reed, R, Gillis, M K, Parent, B, Liu, B, Sztupinszki, Z, Birkbak, N, Szallasi, Z, Elia, A E H, Garber, J E & Pathania, S 2020, ' E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells ', The Journal of Cell Biology, vol. 219, no. 6, e201908192 . https://doi.org/10.1083/jcb.201908192 |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | BRCA1/2 help maintain genomic integrity by stabilizing stalled forks for repair and thus act as tumor suppressors. Duan et al. identify the E3 ligase RFWD3 as a novel modulator of stalled fork stability in BRCA2-deficient cells and show that blocking fork degradation by depleting MRE11 is not sufficient for full fork recovery. 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. |
| Databáze: | OpenAIRE |
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