Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Mol Cell. 2024 Feb 1;84(3):447-462.e10. doi: 10.1016/j.molcel.2023.12.025. Epub 2024 Jan 19.
Tumor suppressor BRCA2 functions in homology-directed repair (HDR), the protection of stalled replication forks, and the suppression of replicative gaps, but their relative contributions to genome integrity and chemotherapy response are under scrutiny. Here, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for fork protection and gap suppression but not HDR. In mice, the loss of fork protection/gap suppression does not compromise genome stability or shorten tumor latency. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection/gap suppression defects are also observed in Brca2 heterozygous cells, likely due to reduced RAD51 stabilization at stalled forks/gaps. Gaps arise from PRIMPOL activity, which is associated with 5-hydroxymethyl-2'-deoxyuridine sensitivity due to the formation of SMUG1-generated abasic sites and is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition. However, HDR proficiency has the major role in mitigating sensitivity to chemotherapeutics, including PARP inhibitors.
抑癌基因 BRCA2 参与同源重组修复（HDR）、停滞复制叉的保护以及复制间隙的抑制，但它们对基因组完整性和化疗反应的相对贡献仍在研究之中。在这里，我们报告称，小鼠和人类细胞需要 BRCA2 中的 RAD51 丝稳定基序来进行叉保护和间隙抑制，但不需要 HDR。在小鼠中，叉保护/间隙抑制的丧失不会损害基因组稳定性或缩短肿瘤潜伏期。相比之下，HDR 缺陷会增加自发和复制应激诱导的染色体畸变以及肿瘤易感性。与 HDR 不同，Brca2 杂合细胞中也观察到叉保护/间隙抑制缺陷，这可能是由于停滞叉/间隙处 RAD51 稳定性降低所致。间隙是由 PRIMPOL 活性引起的，由于形成 SMUG1 产生的无碱基位点，PRIMPOL 活性与 5-羟甲基-2'-脱氧尿苷敏感性相关，并且会被聚（ADP-核糖）聚合酶（PARP）抑制剂加剧。然而，HDR 效率在减轻对化疗药物（包括 PARP 抑制剂）的敏感性方面起着主要作用。
