Breast cancer brain metastasis (BCBM) is a devastating disease. Radiation therapy remains the mainstay for treatment of this disease. Unfortunately, its efficacy is limited by the dose that can be safely applied. One promising approach to overcoming this limitation is to sensitize BCBMs to radiation by inhibiting their ability to repair DNA damage. Here, we report a DNA repair suppressor, leucine-rich repeat-containing protein 31 (LRRC31), that was identified through a genome-wide CRISPR screen. We found that overexpression of LRRC31 suppresses DNA repair and sensitizes BCBMs to radiation. Mechanistically, LRRC31 interacts with Ku70/Ku80 and the ataxia telangiectasia mutated and RAD3-related (ATR) at the protein level, resulting in inhibition of DNA-dependent protein kinase, catalytic subunit (DNA–PKcs) recruitment and activation, and disruption of the MutS homologue 2 (MSH2)–ATR module. We demonstrate that targeted delivery of the LRRC31 gene via nanoparticles improves the survival of tumour-bearing mice after irradiation. Collectively, our study suggests LRRC31 as a major DNA repair suppressor that can be targeted for cancer radiosensitizing therapy.

乳腺癌脑转移（BCBM）是一种毁灭性疾病。放射治疗仍然是治疗这种疾病的主要方法。不幸的是，它的功效受到可以安全使用的剂量的限制。克服这一限制的一种有希望的方法是通过抑制 BCBM 修复 DNA 损伤的能力来使它们对辐射敏感。在这里，我们报告了一种 DNA 修复抑制因子，富含亮氨酸的重复蛋白 31 (LRRC31)，它是通过全基因组 CRISPR 筛选鉴定的。我们发现LRRC31的过表达抑制 DNA 修复并使 BCBM 对辐射敏感。从机制上讲，LRRC31 与 Ku70/Ku80 和共济失调毛细血管扩张症在蛋白质水平上发生突变和 RAD3 相关 (ATR) 相互作用，导致抑制 DNA 依赖性蛋白激酶、催化亚基 (DNA-PKcs) 募集和激活，以及破坏MutS 同源物 2 (MSH2)–ATR 模块。我们证明了通过纳米颗粒靶向递送LRRC31基因可以提高辐射后荷瘤小鼠的存活率。总的来说，我们的研究表明 LRRC31 是一种主要的 DNA 修复抑制因子，可以作为癌症放射增敏治疗的靶点。