Homology-directed repair: BRCA2 and RAD51 paralogs

项目摘要/摘要 同源重组，即同源定向修复，是双链修复的主要途径 断裂(DSB)，包括DNA复制过程中出现的损伤。HDR突变体的基因组特征 对DNA损伤剂如顺铂和链间交联剂的不稳定性和敏感性 聚(ADP-核糖)聚合酶抑制剂，这两种药物都用于癌症治疗。几种蛋白质的核心 HDR途径是肿瘤抑制因子，特别是乳腺癌和卵巢癌抑制因子BRCA2，它 促进RAD51的功能，RAD51是同源链交换的关键蛋白质。RAD51 Paralog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是 杂合子，但肿瘤典型的体细胞经历杂合性丢失(LOH)，失去野生型 等位基因，可能是肿瘤发生的早期步骤。 这项提议的首要目标是整合我们对HDR蛋白质如何作用于 维持基因组稳定性和细胞和组织的动态平衡，它们是如何在细胞中“丢失”的，以及它们是如何 功能可以恢复。因此，这个广泛的目标影响肿瘤的启动、治疗反应和治疗。 抵抗。它结合了对HDR蛋白功能的分子分析，特别关注BRCA2，以及 描绘了细胞如何对HDR蛋白丢失做出反应，包括它们如何逃脱细胞死亡以允许肿瘤 队形。这一目标是从确定肿瘤发生机制的角度来理解肿瘤的发生 导致HDR蛋白丢失的杂合性缺失，以及影响杂合性缺失频率的因素。而HDR 蛋白质丢失使肿瘤对靶向治疗敏感，HDR功能通常通过二次突变恢复， 导致治疗抵抗。了解哪些突变容易逆转以及如何治疗 Impact恢复是一个重要的问题。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，这被认为是高级别浆膜的起源组织。 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.