ArticlePLoS biology2021
Loss of the abasic site sensor HMCES is synthetic lethal with the activity of the APOBEC3A cytosine deaminase in cancer cells.
Article in PLoS biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 40 citations in OpenAlex.
- Unraveling the lexicon of complex mutational phenomena in human cancers.Nature cancer · 2026Review
- Squamous-state excursions activate APOBEC3A in cancer.bioRxiv : the preprint server for biology · 2026Article
- APOBEC3A-Induced DNA Damage Drives Polymerase θ Dependency and Synthetic Lethality in Cancer.bioRxiv : the preprint server for biology · 2025Article
- Joint inference of mutational signatures from indels and single-nucleotide substitutions reveals prognostic impact of DNA repair deficiencies.Genome medicine · 2025Article
- HMCES corrupts replication fork stability during base excision repair in homologous recombination-deficient cells.Science advances · 2025Article
- Contributing factors to the oxidation-induced mutational landscape in human cells.Nature communications · 2024Article
- Review
- The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.The EMBO journal · 2024Article
- APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability.Science advances · 2024Article
- Self-reversal facilitates the resolution of HMCES DNA-protein crosslinks in cells.Cell reports · 2023Article
- A non-proteolytic release mechanism for HMCES-DNA-protein crosslinks.The EMBO journal · 2023Article
- Genetic inhibitors of APOBEC3B-induced mutagenesis.Genome research · 2023Article
- Novel mechanisms for the removal of strong replication-blocking HMCES- and thiazolidine-DNA adducts in humans.Nucleic acids research · 2023Article
- Clinical Implications of APOBEC3-Mediated Mutagenesis in Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Review
- Article
- APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential.Journal of hematology & oncology · 2023Review
- Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer.Nature genetics · 2022Review
- TP53-dependent toxicity of CRISPR/Cas9 cuts is differential across genomic loci and can confound genetic screening.Nature communications · 2022Article
- FANCD2 maintains replication fork stability during misincorporation of the DNA demethylation products 5-hydroxymethyl-2'-deoxycytidine and 5-hydroxymethyl-2'-deoxyuridine.Cell death & disease · 2022Article
- DNA repair defects in cancer and therapeutic opportunities.Genes & development · 2022Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.