LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la protéine LRRC31 inhibe la réparation de l'ADN et sensibilise aux rayonnements ionisants les métastases cérébrales ayant pour origine un cancer du sein
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.
Nature Cell Biology 2020