Loss of the abasic site sensor HMCES is synthetic lethal with the activity of the APOBEC3A cytosine deaminase in cancer cells.
Adenocarcinoma of Lung
/ genetics
Ataxia Telangiectasia Mutated Proteins
/ metabolism
Carcinoma, Non-Small-Cell Lung
/ genetics
Cell Line, Tumor
Checkpoint Kinase 1
/ metabolism
Cytidine Deaminase
/ genetics
Cytosine Deaminase
/ genetics
DNA
/ genetics
DNA Damage
/ genetics
DNA Replication
/ genetics
DNA-Binding Proteins
/ genetics
Humans
Proteins
/ genetics
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
24
07
2020
accepted:
08
03
2021
revised:
12
04
2021
pubmed:
1
4
2021
medline:
27
7
2021
entrez:
31
3
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33788831
doi: 10.1371/journal.pbio.3001176
pii: PBIOLOGY-D-20-02244
pmc: PMC8041192
doi:
Substances chimiques
DNA-Binding Proteins
0
HMCES protein, human
0
Proteins
0
DNA
9007-49-2
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
CHEK1 protein, human
EC 2.7.11.1
Checkpoint Kinase 1
EC 2.7.11.1
Cytosine Deaminase
EC 3.5.4.1
APOBEC3A protein, human
EC 3.5.4.5
Cytidine Deaminase
EC 3.5.4.5
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3001176Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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