Homology-directed repair: BRCA2 and RAD51 paralogs

项目概要/摘要 同源重组，即，同源性定向修复（HDR）是双链损伤的主要修复途径， 断裂（DSB），包括DNA复制过程中出现的病变。HDR突变体的特征在于基因组 不稳定性和对DNA损伤剂如链间交联剂如顺铂和 聚（ADP-核糖）聚合酶抑制剂，两者都用于癌症治疗。几种蛋白质 HDR通路是肿瘤抑制因子，特别是乳腺癌和卵巢癌抑制因子BRCA 2， 促进同源链交换的关键蛋白质RAD 51的功能。RAD 51旁系同源物是 也是关键的HDR蛋白，也被鉴定为肿瘤抑制因子和影响 治疗反应这些HDR蛋白是必不可少的。具有生殖系突变的个体在体质上 杂合性，但肿瘤通常具有经历杂合性丢失（洛）的体细胞，失去野生型 等位基因，可能是肿瘤发生的早期步骤。 该提案的总体目标是整合我们对HDR蛋白如何发挥作用的理解， 维持基因组稳定性和细胞及组织的稳态，它们如何在细胞中“丢失”，以及它们如何在细胞中“丢失”。 功能可以恢复。因此，这一广泛的目标影响了肿瘤的起始、治疗反应和治疗效果。 阻力它结合了HDR蛋白功能的分子分析，特别关注BRCA 2， 描绘了细胞如何应对HDR蛋白的损失，包括它们如何逃避细胞死亡， 阵在这个目标中，从确定肿瘤发生机制的角度来理解肿瘤的发生。 导致HDR蛋白丢失的洛，以及揭示影响洛频率的因素。虽然HDR 蛋白质丢失使肿瘤对靶向治疗敏感，HDR功能通常通过继发突变恢复， 导致治疗抵抗。了解哪些突变容易逆转以及如何治疗 影响恢复是主要的兴趣。最后，组织内的HDR也是这一综合目标的一部分， 特别是在输卵管上皮内，这被认为是高级浆液性卵巢癌的起源组织。 卵巢癌

Project Summary/Abstract Homologous recombination, i.e., homology-directed repair (HDR), is a major repair pathway for double-strand breaks (DSBs), including lesions arising during DNA replication. HDR mutants are characterized by genomic instability and sensitivity to DNA damaging agents such as interstrand cross-linking agents like cisplatin and poly(ADP-ribose) polymerase inhibitors, both of which are used in cancer treatment. Several proteins central to the HDR pathway are tumor suppressors, notably the breast and ovarian cancer suppressor BRCA2, which promotes the function of RAD51, the critical protein for homologous strand exchange. RAD51 paralogs are also key HDR proteins and have also been identified both as tumor suppressors and as proteins that affect therapy response. These HDR proteins are essential. Individuals with germline mutations are constitutionally heterozygous, but tumors typically have somatic undergone loss of heterozygosity (LOH), losing the wild-type allele, presumably as an early step in tumor initiation. This proposal has an overarching goal of integrating our understanding how HDR proteins act to maintain genomic stability and cell and tissue homeostasis, how they come to be “lost” in cells, and how their function can be restored. Thus, this broad goal impacts tumor initiation, therapy response, and therapy resistance. It incorporates molecular analysis of HDR protein function, with a particular focus on BRCA2, and delineates how cells respond to HDR protein loss, including how they escape cell death to allow tumor formation. Within this goal is understanding tumor initiation from the standpoint of determining mechanisms of LOH that lead to HDR protein loss, as well as uncovering factors that affect LOH frequencies. While HDR protein loss sensitizes tumors to targeted therapies, HDR function is often restored by secondary mutations, leading to therapy resistance. Understanding which mutations are susceptible to reversion and how therapy impacts reversion is of major interest. Finally, HDR within tissues is also part of this integrated goal, in particular, within the fallopian tube epithelium, which is considered the tissue of origin of high-grade serous ovarian cancers.