Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Nucleic Acids Res. 2021 Apr 6;49(6):3322-3337. doi: 10.1093/nar/gkab134.
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.
RPA 是 DNA 复制和复制应激反应的关键因素。令人惊讶的是，我们发现染色质 RPA 的稳定性受到严格调控。我们报告说，GDP/GTP 交换因子 DOCK7 作为一个关键的复制应激调节剂，促进染色质上 RPA 的稳定性。ATR 磷酸化 DOCK7 后，MDC1 在复制应激时将其募集到染色质和复制叉。DOCK7 介导的 Rac1/Cdc42 激活导致 PAK1 的激活，随后 PAK1 将 RPA1 的 S135 和 T180 磷酸化，稳定染色质结合的 RPA1，确保适当的复制应激反应。此外，DOCK7 在卵巢癌中过表达，敲低 DOCK7 可使癌细胞对喜树碱敏感。总之，我们的研究结果突出了 DOCK7 在调节复制应激反应中的新作用，并强调了克服癌症化疗耐药性的潜在治疗靶点。
