LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy.

Abstract

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.

• Authors: Yanke Chen, Ting Jiang, Hongyi Zhang, Xingchun Gou, Cong Han, Jianhui Wang, Ann T Chen, Jun Ma, Jun Liu, Zeming Chen, Xintao Jing, Hong Lei, Zhenzhen Wang, Youmei Bao, Mehdi Baqri, Yong Zhu, Ranjit S Bindra, James E Hansen, Jun Dou, Chen Huang, Jiangbing Zhou
• Journal: Nature cell biology (Nat Cell Biol) Vol. 22 Issue 10 Pg. 1276-1285 (10 2020) ISSN: 1476-4679 [Electronic] England
• PMID: 33005030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• LRRC31 protein, human
• Nuclear Proteins
• Radiation-Sensitizing Agents
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• MSH2 protein, human
• MutS Homolog 2 Protein

Topics

• Animals
• Apoptosis
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
• Brain Neoplasms (metabolism, radiotherapy, secondary)
• Breast Neoplasms (metabolism, pathology, radiotherapy)
• Cell Proliferation
• DNA Damage
• DNA Repair
• Female
• Gamma Rays
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MutS Homolog 2 Protein (genetics, metabolism)
• Nuclear Proteins (administration & dosage, metabolism)
• Phosphorylation
• Radiation-Sensitizing Agents (administration & dosage, metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays