The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.
Cancer Mutagenesis
Cytidine Deaminase
Genome Integrity
Mutational Signatures
Replication Stress
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
17 Jun 2024
17 Jun 2024
Historique:
received:
22
01
2024
accepted:
17
05
2024
revised:
09
05
2024
medline:
18
6
2024
pubmed:
18
6
2024
entrez:
17
6
2024
Statut:
aheadofprint
Résumé
Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.
Identifiants
pubmed: 38886582
doi: 10.1038/s44318-024-00137-x
pii: 10.1038/s44318-024-00137-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA248526
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : HHS | National Institutes of Health (NIH)
ID : R01CA237263
Organisme : HHS | National Institutes of Health (NIH)
ID : R01CA248526
Organisme : NHLBI NIH HHS
ID : T32 HL007088
Pays : United States
Organisme : U.S. Department of Defense (DOD)
ID : CA200867
Organisme : NCI NIH HHS
ID : K08 CA212299
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237263
Pays : United States
Informations de copyright
© 2024. The Author(s).
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