Nucleic acids research, 2021-04, Vol.49 (6), p.3322-3337
2021
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Details
- Autor(en) / Beteiligte
- Titel
- DOCK7 protects against replication stress by promoting RPA stability on chromatin
- Ist Teil von
- Nucleic acids research, 2021-04, Vol.49 (6), p.3322-3337
- Ort / Verlag
- England
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0305-1048eISSN: 1362-4962DOI: 10.1093/nar/gkab134Titel-ID: cdi_pubmed_primary_33704464
- Format
- –
- Schlagworte
- Animals, cdc42 GTP-Binding Protein - metabolism, Cell Line, Tumor, Chromatin - metabolism, DNA Repair, DNA Replication, Female, GTPase-Activating Proteins - antagonists & inhibitors, GTPase-Activating Proteins - metabolism, GTPase-Activating Proteins - physiology, Guanine Nucleotide Exchange Factors - antagonists & inhibitors, Guanine Nucleotide Exchange Factors - metabolism, Guanine Nucleotide Exchange Factors - physiology, HEK293 Cells, Humans, Mice, Mice, Nude, Ovarian Neoplasms - drug therapy, Ovarian Neoplasms - metabolism, p21-Activated Kinases - metabolism, Phosphorylation, Proteolysis, rac1 GTP-Binding Protein - metabolism, Replication Protein A - metabolism, Signal Transduction, Stress, Physiological - genetics