Loss of the abasic site sensor HMCES is synthetic lethal with the activity of the APOBEC3A cytosine deaminase in cancer cells

PLoS Biol. 2021 Mar 31;19(3):e3001176. doi: 10.1371/journal.pbio.3001176. eCollection 2021 Mar.

Abstract

Analysis of cancer mutagenic signatures provides information about the origin of mutations and can inform the use of clinical therapies, including immunotherapy. In particular, APOBEC3A (A3A) has emerged as a major driver of mutagenesis in cancer cells, and its expression results in DNA damage and susceptibility to treatment with inhibitors of the ATR and CHK1 checkpoint kinases. Here, we report the implementation of CRISPR/Cas-9 genetic screening to identify susceptibilities of multiple A3A-expressing lung adenocarcinoma (LUAD) cell lines. We identify HMCES, a protein recently linked to the protection of abasic sites, as a central protein for the tolerance of A3A expression. HMCES depletion results in synthetic lethality with A3A expression preferentially in a TP53-mutant background. Analysis of previous screening data reveals a strong association between A3A mutational signatures and sensitivity to HMCES loss and indicates that HMCES is specialized in protecting against a narrow spectrum of DNA damaging agents in addition to A3A. We experimentally show that both HMCES disruption and A3A expression increase susceptibility of cancer cells to ionizing radiation (IR), oxidative stress, and ATR inhibition, strategies that are often applied in tumor therapies. Overall, our results suggest that HMCES is an attractive target for selective treatment of A3A-expressing tumors.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / metabolism
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / metabolism
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / metabolism
  • Cytosine Deaminase / genetics
  • Cytosine Deaminase / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage / genetics
  • DNA Damage / physiology
  • DNA Replication / genetics
  • DNA Replication / physiology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Proteins / genetics*
  • Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • HMCES protein, human
  • Proteins
  • DNA
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Cytosine Deaminase
  • APOBEC3A protein, human
  • Cytidine Deaminase

Grant support

J.B., M.M. and F.S. were supported by the ERC Starting Grant (757700 “HYPER-INSIGHT”, to F.S). I.G.C. was funded by an AECC fellowship. M.M.A. and J.E.C. were supported by the Spanish Ministry of Science, Innovation and Universities (BFU2017-89833-P "RegioMut", to F.S.). T.H.S. was funded by the Spanish Ministry of Science, Innovation and Universities (MCIU: PGC2018-095616-B-I00/GINDATA and FEDER) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The T.H.S. and F.S. labs are supported by the Centres of Excellence Severo Ochoa award and the CERCA Programme. F.S. is funded by the ICREA Research Professor programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.