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

Kunming Zhao; Xingwen Wang; Xuting Xue; Li Li; Ying Hu

doi:10.1371/journal.pbio.3000666

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

PLoS Biol. 2020 Mar 23;18(3):e3000666. doi: 10.1371/journal.pbio.3000666. eCollection 2020 Mar.

Authors

Kunming Zhao¹, Xingwen Wang¹, Xuting Xue¹, Li Li², Ying Hu^{1

3}

Affiliations

¹ School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, China.
² The fourth affiliated hospital, Harbin Medical University, Harbin, Heilongjiang Province, China.
³ Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acid Anhydride Hydrolases / metabolism
Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
Ataxia Telangiectasia Mutated Proteins / genetics
Ataxia Telangiectasia Mutated Proteins / metabolism*
Binding Sites
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
DNA Breaks, Double-Stranded / drug effects
DNA Damage*
DNA-Binding Proteins / metabolism
Early Growth Response Protein 1 / genetics
Early Growth Response Protein 1 / metabolism
HCT116 Cells
HeLa Cells
Humans
MRE11 Homologue Protein / metabolism
Mice
Mice, Nude
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Phosphorylation
Protein Binding
RNA, Long Noncoding / genetics
RNA, Long Noncoding / metabolism*
Recombinational DNA Repair / genetics*
Transcription, Genetic / drug effects

Substances

Antineoplastic Agents
Cell Cycle Proteins
DNA-Binding Proteins
EGR1 protein, human
Early Growth Response Protein 1
MRE11 protein, human
NBN protein, human
Nuclear Proteins
RNA, Long Noncoding
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
MRE11 Homologue Protein
Acid Anhydride Hydrolases
RAD50 protein, human

Grants and funding

This work was supported by National Natural Science Foundation of China (31871389, 31301131, and 31741084) and the Basic Science Foundation of the Shenzhen Science, Technology and Innovation Commission (JCYJ20170811154452255) (received by YH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.