Herrera Luis Reza, McGlynn Kathleen, Gibbs Zane A, Davis Anthony J, Whitehurst Angelique W
bioRxiv. 2023 Feb 3:2023.01.31.526348. doi: 10.1101/2023.01.31.526348.
Tumors frequently activate the expression of genes that are only otherwise required for meiosis. HORMAD1, which is essential for meiotic recombination in multiple species, is expressed in over 50% of human lung adenocarcinoma cells (LUAD). We previously found that HORMAD1 promotes DNA double strand break (DSB) repair in LUAD. Here, we report that HORMAD1 takes on an additional role in protecting genomic integrity. Specifically, we find HORMAD1 is critical for protecting stalled DNA replication forks in LUAD. Loss of HORMAD1 leads to nascent DNA degradation, an event which is mediated by the MRE11-DNA2-BLM pathway. Moreover, following exogenous induction of DNA replication stress, HORMAD1 deleted cells accumulate single stranded DNA (ssDNA). We find that these phenotypes are the result of a lack of RAD51 and BRCA2 loading onto stalled replication forks. Ultimately, loss of HORMAD1 leads to increased DSBs and chromosomal aberrations in response to replication stress. Collectively, our data support a model where HORMAD1 expression is selected to mitigate DNA replication stress, which would otherwise induce deleterious genomic instability.
肿瘤常常会激活那些通常仅在减数分裂时才需要的基因的表达。HORMAD1在多个物种的减数分裂重组中至关重要，在超过50%的人肺腺癌细胞（LUAD）中表达。我们之前发现HORMAD1促进LUAD中的DNA双链断裂（DSB）修复。在此，我们报告HORMAD1在保护基因组完整性方面发挥了额外作用。具体而言，我们发现HORMAD1对于保护LUAD中停滞的DNA复制叉至关重要。HORMAD1的缺失会导致新生DNA降解，这一事件由MRE11 - DNA2 - BLM途径介导。此外，在外源诱导DNA复制应激后，HORMAD1缺失的细胞会积累单链DNA（ssDNA）。我们发现这些表型是由于RAD51和BRCA2无法加载到停滞的复制叉上所致。最终，HORMAD1的缺失会导致在应对复制应激时DSB增加和染色体畸变。总体而言，我们的数据支持一种模型，即选择HORMAD1表达来减轻DNA复制应激，否则会导致有害的基因组不稳定。
