Chk1 通过直接磷酸化 ASF1A 在 G1 期促进非同源末端连接。
Chk1 promotes non-homologous end joining in G1 through direct phosphorylation of ASF1A.
机构信息
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22901, USA; Division of Cancer Biology, Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do 10408, South Korea.
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22901, USA.
出版信息
Cell Rep. 2021 Jan 26;34(4):108680. doi: 10.1016/j.celrep.2020.108680.
The cell-cycle phase is a major determinant of repair pathway choice at DNA double strand breaks, non-homologous end joining (NHEJ), or homologous recombination (HR). Chk1 responds to genotoxic stress in S/G2 phase, but here, we report a role of Chk1 in directly promoting NHEJ repair in G1 phase. ASF1A is a histone chaperone, but it promotes NHEJ through a pathway independent of its histone-chaperone activity. Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. Chk1 deficiency suppresses all steps downstream of MDC1 following a DNA break in G1, namely histone ubiquitination, 53BP1 localization to the DNA break, and NHEJ. Thus, ASF1A phosphorylation by Chk1 is essential for DNA break repair by NHEJ in G1.
细胞周期阶段是决定 DNA 双链断裂修复途径选择的主要因素，包括非同源末端连接（NHEJ）或同源重组（HR）。Chk1 在 S/G2 期对遗传毒性应激做出反应，但在这里，我们报告了 Chk1 在 G1 期直接促进 NHEJ 修复的作用。ASF1A 是一种组蛋白伴侣，但它通过不依赖其组蛋白伴侣活性的途径促进 NHEJ。在 G1 期，ATM 激酶在 DNA 断裂处激活的 Chk1 通过直接磷酸化 ASF1A 的丝氨酸 166 来促进 NHEJ。磷酸化丝氨酸 166 的 ASF1A 与修复蛋白 MDC1 相互作用，从而增强 MDC1 与 ATM 的相互作用和 ATM 在 DNA 断裂处的稳定定位。Chk1 缺陷抑制了 G1 期 DNA 断裂后 MDC1 下游的所有步骤，即组蛋白泛素化、53BP1 定位到 DNA 断裂处和 NHEJ。因此，Chk1 对 ASF1A 的磷酸化对于 G1 期 NHEJ 修复至关重要。
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