A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers

Zhao, Kunming and Wang, Xingwen and Xue, Xuting and Li, Li and Hu, Ying and Paull, Tanya (2020) A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers. PLOS Biology, 18 (3). e3000666. ISSN 1545-7885

[thumbnail of file_id=10.1371%2Fjournal.pbio.3000666&type=printable] Text
file_id=10.1371%2Fjournal.pbio.3000666&type=printable - Published Version

Download (4MB)

Abstract

Ataxia-telangiectasia mutated (ATM) is an apical kinase of the DNA damage response following DNA double-strand breaks (DSBs); however, the mechanisms of ATM activation are not completely understood. Long noncoding RNAs (lncRNAs) are a class of regulatory molecules whose significant roles in DNA damage response have started to emerge. However, how lncRNA regulates ATM activity remains unknown. Here, we identify an inhibitor of ATM activation, lncRNA HITT (HIF-1α inhibitor at translation level). Mechanistically, HITT directly interacts with ATM at the HEAT repeat domain, blocking MRE11-RAD50-NBS1 complex–dependent ATM recruitment, leading to restrained homologous recombination repair and enhanced chemosensitization. Following DSBs, HITT is elevated mainly by the activation of Early Growth Response 1 (EGR1), resulting in retarded and restricted ATM activation. A reverse association between HITT and ATM activity was also detected in human colon cancer tissues. Furthermore, HITTs sensitize DNA damaging agent–induced cell death both in vitro and in vivo. These findings connect lncRNA directly to ATM activity regulation and reveal potential roles for HITT in sensitizing cancers to genotoxic treatment.

Item Type: Article
Subjects: Science Repository > Biological Science
Depositing User: Managing Editor
Date Deposited: 23 Jan 2023 05:32
Last Modified: 02 Apr 2024 04:03
URI: http://research.manuscritpub.com/id/eprint/1348

Actions (login required)

View Item
View Item