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- Title
Loss of the abasic site sensor HMCES is synthetic lethal with the activity of the APOBEC3A cytosine deaminase in cancer cells.
- Authors
Biayna, Josep; Garcia-Cao, Isabel; Álvarez, Miguel M.; Salvadores, Marina; Espinosa-Carrasco, Jose; McCullough, Marcel; Supek, Fran; Stracker, Travis H.
- 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. APOBEC3A (A3A) cytosine deaminase activity causes DNA damage and drives cancer mutagenesis. A genome-scale CRISPR/Cas9 screen identifies HMCES, a suicide enzyme that binds abasic sites, as a major suppressor of A3A-mediated damage in non-small cell lung cancer. Depletion of HMCES is synthetic lethal with A3A expression and p53 loss, suggesting its potential as a drug target.
- Subjects
CANCER cells; CYTOSINE; NON-small-cell lung carcinoma; GENETIC testing; DNA polymerases; DNA damage
- Publication
PLoS Biology, 2021, Vol 19, Issue 3, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3001176