Journal
NATURE CELL BIOLOGY
Volume 22, Issue 10, Pages 1276-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41556-020-00586-6
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Funding
- NCATS NIH HHS [UL1 TR001863] Funding Source: Medline
- NINDS NIH HHS [R01 NS095817] Funding Source: Medline
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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 ofLRRC31suppresses 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 theLRRC31gene 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. LRRC31 links DNA repair and radiation efficacy Chen et al. perform a genome-wide CRIPSR screen and identify LRRC31, which interacts with Ku70/80 to suppress DNA repair and enhances the efficacy of radiation therapy in breast cancer brain metastasis.
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