广泛的不依赖于 BRCA1/2 的同源重组缺陷是由 RNA 结合蛋白的改变引起的。
Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins.
发表日期：2023 Oct 27
作者：
Daniel J McGrail, Yang Li, Roger S Smith, Bin Feng, Hui Dai, Limei Hu, Briana Dennehey, Sharad Awasthi, Marc L Mendillo, Anil K Sood, Gordon B Mills, Shiaw-Yih Lin, S Stephen Yi, Nidhi Sahni
来源：
Epigenetics & Chromatin
摘要：
同源重组 DNA 修复 (HRD) 的缺陷既容易导致癌症发展，也会产生治疗漏洞，因此确定导致 HRD 的遗传事件范围至关重要。然而，我们发现 BRCA1/2 和其他典型 HR 基因的突变仅识别出 10%-20% 的显示 HRD 基因组证据的肿瘤。使用基于网络的方法，我们发现超过一半的导致 HRD 的推定基因起源于经典 DNA 损伤反应基因之外，其中特别富集 RNA 结合蛋白 (RBP) 编码基因。这些假定的 HRD 驱动因素经过实验验证，在独立队列中进行交叉验证，并在与癌症相关的全基因组关联研究位点中丰富。机制研究表明，一些 RBP 被招募到 DNA 损伤位点以促进修复，而其他 RBP 则控制典型 HR 基因的表达。总体而言，这项研究极大地扩展了 HRD 的已知驱动因素，对基础生物学、基因筛查和治疗分层具有影响。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。
Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%-20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated genome-wide association study loci. Mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.