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.
Highlights
Cells are inevitably challenged by endogenous or exogenous sources of DNA damage [1]
HIF-1α inhibitor at translation level (HITT) was significantly increased by drugs that have been reported to induce doublestrand break (DSB), such as doxorubicin (Dox), etoposide (Eto), the radiomimetic compound bleomycin (Bleo), and calicheamicin (CLA) [32,33,34], but not DSB-independent pro-death treatments, such as tumor necrosis factor-α (TNF-α)/cycloheximide (CHX) and taxol, similar death rates were induced (Fig 1A)
We found that HITT overexpression markedly inhibited homologous recombination (HR), as indicated by Direct Repeat (DR)-green fluorescent protein (GFP), but not nonhomologous end joining (NHEJ), as indicated by EJ2- and EJ5-GFP (Fig 1F and 1G)
Summary
Cells are inevitably challenged by endogenous or exogenous sources of DNA damage [1]. Organisms have evolved elegant mechanisms to cope with various forms of DNA damage, collectively known as the DNA damage response (DDR) [2]. Deficiency in the DDR is associated with genomic instability, predisposition to cancer, or cell death in cases when damage is irreparable [3]. DNA damage represents the backbone of cancer treatment. In this context, activation of DNA damage repair pathways promotes genotoxic resistance, which remains a major obstacle in successful cancer treatment [4,5]. Unveiling the mechanisms underlying the DDR may inform our knowledge of tumorigenesis and provide predictive markers for the patients’ responses to therapeutic DNA damage and offer new opportunities for the improvement of treatment efficiency
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