LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy.
LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy.
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DOI：
10.1038/s41556-020-00586-6
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发表时间：
2020-10
影响因子：
21.3
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Chen Y;Jiang T;Zhang H;Gou X;Han C;Wang J;Chen AT;Ma J;Liu J;Chen Z;Jing X;Lei H;Wang Z;Bao Y;Baqri M;Zhu Y;Bindra RS;Hansen JE;Dou J;Huang C;Zhou J
乳腺癌脑转移（BCBM）是一种毁灭性疾病。放射疗法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。克服这一限制的一个有希望的方法是通过抑制BCBMs修复DNA损伤的能力使其对辐射敏感。在这里，我们报告了一种DNA修复抑制因子，富含亮氨酸的重复序列蛋白31 (LRRC31)，通过全基因组CRISPR筛选鉴定。我们发现LRRC31的过表达抑制DNA修复并使BCBMs对辐射敏感。从机制上讲，LRRC31在蛋白水平上与Ku70/Ku80和ATR相互作用，抑制DNA-PKcs的募集和激活，破坏MSH2-ATR模块。我们证明，通过纳米颗粒靶向递送LRRC31基因显著提高了照射后荷瘤小鼠的存活率。总之，我们的研究表明LRRC31是一种主要的DNA修复抑制因子，可以靶向癌症放射增敏治疗。
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 ATR at the protein level, resulting in inhibition of DNA-PKcs recruitment and activation, and disruption of the MSH2-ATR module. We demonstrated that targeted delivery of LRRC31 gene via nanoparticles significantly improved the survival of tumor-bearing mice after irradiation. Collectively, our study suggests LRRC31 as a major DNA repair suppressor that can be targeted for cancer radiosensitizing therapy.
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