Open AccessLRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy
Author(s) -
Yanke Chen,
Ting Jiang,
Hongyi Zhang,
Xin Gou,
Cong Han,
Jianhui Wang,
Ann T. Chen,
Jun Ma,
Jun Li,
Zeming Chen,
Xinli Jing,
Hong Lei,
Zhenzhen Wang,
Yun-Juan Bao,
Mehdi Baqri,
Yong Zhu,
Ranjit S. Bindra,
James E. Hansen,
Jun Dou,
Chen Huang,
Jiangbing Zhou
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-00586-6
Subject(s) - ku70 , dna repair , cancer research , dna damage , ku80 , biology , cancer , radiosensitizer , radiation therapy , msh2 , non homologous end joining , dna , medicine , gene , dna mismatch repair , dna binding protein , genetics , transcription factor
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.