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LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962994/ https://www.ncbi.nlm.nih.gov/pubmed/33005030 http://dx.doi.org/10.1038/s41556-020-00586-6 |
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author | Chen, Yanke Jiang, Ting Zhang, Hongyi Gou, Xingchun Han, Cong Wang, Jianhui Chen, Ann T. Ma, Jun Liu, Jun Chen, Zeming Jing, Xintao Lei, Hong Wang, Zhenzhen Bao, Youmei Baqri, Mehdi Zhu, Yong Bindra, Ranjit S. Hansen, James E. Dou, Jun Huang, Chen Zhou, Jiangbing |
author_facet | Chen, Yanke Jiang, Ting Zhang, Hongyi Gou, Xingchun Han, Cong Wang, Jianhui Chen, Ann T. Ma, Jun Liu, Jun Chen, Zeming Jing, Xintao Lei, Hong Wang, Zhenzhen Bao, Youmei Baqri, Mehdi Zhu, Yong Bindra, Ranjit S. Hansen, James E. Dou, Jun Huang, Chen Zhou, Jiangbing |
author_sort | Chen, Yanke |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7962994 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-79629942021-04-01 LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy Chen, Yanke Jiang, Ting Zhang, Hongyi Gou, Xingchun Han, Cong Wang, Jianhui Chen, Ann T. Ma, Jun Liu, Jun Chen, Zeming Jing, Xintao Lei, Hong Wang, Zhenzhen Bao, Youmei Baqri, Mehdi Zhu, Yong Bindra, Ranjit S. Hansen, James E. Dou, Jun Huang, Chen Zhou, Jiangbing Nat Cell Biol Article 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. 2020-10-01 2020-10 /pmc/articles/PMC7962994/ /pubmed/33005030 http://dx.doi.org/10.1038/s41556-020-00586-6 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Chen, Yanke Jiang, Ting Zhang, Hongyi Gou, Xingchun Han, Cong Wang, Jianhui Chen, Ann T. Ma, Jun Liu, Jun Chen, Zeming Jing, Xintao Lei, Hong Wang, Zhenzhen Bao, Youmei Baqri, Mehdi Zhu, Yong Bindra, Ranjit S. Hansen, James E. Dou, Jun Huang, Chen Zhou, Jiangbing LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy |
title | LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy |
title_full | LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy |
title_fullStr | LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy |
title_full_unstemmed | LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy |
title_short | LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy |
title_sort | lrrc31 inhibits dna repair and sensitizes breast cancer brain metastasis to radiation therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962994/ https://www.ncbi.nlm.nih.gov/pubmed/33005030 http://dx.doi.org/10.1038/s41556-020-00586-6 |
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