PO.MCB05.01 · 分子与细胞生物学
癌睾丸抗原HORMAD1促进肺腺癌中的基因组稳定性
The cancer testis antigen, HORMAD1, promotes genomic stability in lung adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌睾丸抗原（CTAs）是一类表达通常局限于睾丸、但在癌症中异常表达的蛋白。已知的CTAs超过200种，其中大多数在癌症中无已知功能。在睾丸中，HORMA结构域蛋白1（HORMAD1）在减数分裂细胞中表达，并在交叉互换过程中招募蛋白至姐妹染色体以进行遗传信息交换。HORMAD1为交叉互换所必需，缺乏HORMAD1的小鼠健康但不育。HORMAD1在约50%的肺腺癌患者样本中异常表达。患者肿瘤表达数据显示，高HORMAD1表达与患者总生存不良及突变负荷增加相关。HORMAD1阳性肿瘤富集DNA复制应激反应和DNA修复所必需的基因，包括MRE11和RAD51。HORMAD1促进RAD51纤维的形成，后者响应复制应激而累积。癌细胞经历慢性复制应激，并能够在规避灾难性DNA损伤的同时增殖。为确定HORMAD1是否直接与参与DNA代谢的蛋白相关联，我们进行了免疫沉淀质谱分析，发现内源性HORMAD1与参与复制应激反应的一部分蛋白相关联。我们发现缺乏HORMAD1的细胞发生新生DNA链降解，此过程由MRE11-DNA2-BLM通路介导。此外，我们发现HORMAD1保护被F-Box DNA解旋酶1（FBH1）重塑的停滞复制叉，以维持复制叉稳定性。FBH1通过将RAD51从DNA上置换和/或通过泛素化降解，负向调节RAD51的活性。我们发现HORMAD1缺失导致复制期间出现单链DNA缺口。此外，我们发现HORMAD1保护复制期间FBH1介导的缺口，但HORMAD1如何保护这些缺口的机制尚不清楚。我们假设HORMAD1在复制期间将RAD51招募至FBH1介导的单链缺口，以保护这些缺口免于降解并促进基因组稳定性。我们的数据提示，异常的HORMAD1表达减少复制应激诱导的DNA损伤累积，从而预防基因组不稳定。这项研究深入揭示了HORMAD1促进基因组稳定性的机制，以及如何将该过程作为肺腺癌治疗的靶点。
查看英文原文 English abstract
Cancer-testis antigens (CTAs) are proteins whose expressions are typically restricted to the testes but are aberrantly expressed in cancer. There are over 200 known CTAs, most of which have no known function in cancer. In the testis, HORMA Domain Containing Protein 1 (HORMAD1) is expressed in meiotic cells, and recruits proteins to sister chromosomes for the exchange of genetic information during crossing over. HORMAD1 is necessary for crossing over, and mice lacking HORMAD1 are healthy, yet infertile. HORMAD1 is aberrantly expressed in approximately 50% of lung adenocarcinoma patient samples. Patient tumor expression data reveal that high HORMAD1 expression correlates with poor overall patient survival and increased mutational burden. HORMAD1-positive tumors are enriched for genes essential for the DNA replication stress response and DNA repair, including MRE11 and RAD51. HORMAD1 promotes the formation of RAD51 filaments, which accumulate in response to replication stress. Cancer cells undergo chronic replication stress and are able to proliferate while evading catastrophic DNA damage. To determine if HORMAD1 is directly associated with proteins involved in DNA metabolism, we conducted immunoprecipitation mass spectrometry and found that endogenous HORMAD1 associates with a subset of proteins involved in the replication stress response. We found that cells lacking HORMAD1 undergo nascent DNA strand degradation, which is mediated by the MRE11-DNA2-BLM pathway. Moreover, we found that HORMAD1 protects stalled replication forks that are remolded by F-Box DNA Helicase 1 (FBH1) to maintain fork stability. FBH1 negatively regulates the activity of RAD51 via displacement from DNA and/or through ubiquitination for degradation. We found that loss of HORMAD1 leads to single strand DNA gaps during replication. Moreover, we found that HORMAD1 protects FBH1-mediated gaps during replication, but the mechanism as to how HORMAD1 protects these gaps is unknown. We hypothesize that HORMAD1 recruits RAD51 to FBH1-mediated single strand gaps during replication to protect these gaps from degradation and promote genomic stability. Our data suggest that aberrant HORMAD1 expression reduces replication stress-induced DNA damage accumulation to prevent genomic instability. This research gives insight into the mechanism by which HORMAD1 promotes genomic stability and how this process can be targeted for lung adenocarcinoma treatment.
利益披露 Disclosure
R. Johnson, None..
L. Reza Herrera, None.