Cantor Sharon B, Calvo Jennifer A
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605.
Cold Spring Harb Symp Quant Biol. 2017;82:339-348. doi: 10.1101/sqb.2017.82.034413. Epub 2018 Feb 22.
The BRCA-Fanconi anemia (FA) pathway preserves the genome and suppresses cancer and is a main determinant of chemotherapeutic efficacy. The hereditary breast cancer genes and function in DNA double-strand break repair mediating distinct steps of homologous recombination (HR). More recently, independent of DNA repair, functions in the replication stress response have come to light, providing insight as to how the BRCA-FA pathway also balances genome preservation with proliferation. The BRCA-FA proteins associate with the replisome and contribute to the efficiency and recovery of replication following perturbations that slow or arrest DNA replication. Although the full repertoire of functions in the replication stress response remains to be elucidated, the function of and in protecting stalled replication forks contributes along with HR to the sensitivity of BRCA-associated tumors to chemotherapy. Moreover, chemoresistance evolves from restoration of either HR and/or fork protection. Although mechanisms underlying the restoration of HR have been characterized, it remains less clear how restoration of fork protection is achieved. Here, we outline mechanisms of "rewired" fork protection and chemotherapy resistance in BRCA cancer. We propose that mechanisms are linked to permissive replication that limits fork remodeling and therefore opportunities for fork degradation. Combating this chemoresistance mechanism will require drugs that inactivate replication bypass mechanisms.
BRCA-范可尼贫血（FA）通路可维护基因组并抑制癌症，是化疗疗效的主要决定因素。遗传性乳腺癌基因在介导同源重组（HR）不同步骤的DNA双链断裂修复中发挥作用。最近，与DNA修复无关的复制应激反应功能也已被发现，这为BRCA-FA通路如何在基因组维护与细胞增殖之间取得平衡提供了见解。BRCA-FA蛋白与复制体相关联，并在减缓或阻止DNA复制的干扰后，对复制的效率和恢复做出贡献。尽管复制应激反应中的全部功能仍有待阐明，但 和 在保护停滞的复制叉方面的功能与HR一起，导致BRCA相关肿瘤对化疗敏感。此外，化疗耐药性源于HR和/或叉保护的恢复。虽然HR恢复的潜在机制已得到表征，但叉保护的恢复是如何实现的仍不太清楚。在这里，我们概述了BRCA癌症中“重新布线”的叉保护和化疗耐药性机制。我们提出，这些机制与允许性复制有关，这种复制限制了叉重塑，从而减少了叉降解的机会。对抗这种化疗耐药机制将需要使复制旁路机制失活的药物。
