Interaction with the CCT chaperonin complex limits APOBEC3A cytidine deaminase cytotoxicity.
APOBEC3A
CCT chaperonin
cytidine deaminase
mutational signatures
protein interaction
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
06 09 2021
06 09 2021
Historique:
revised:
02
07
2021
received:
22
11
2020
accepted:
05
07
2021
pubmed:
5
8
2021
medline:
8
9
2022
entrez:
4
8
2021
Statut:
ppublish
Résumé
The APOBEC3 cytidine deaminases are implicated as the cause of a prevalent somatic mutation pattern found in cancer genomes. The APOBEC3 enzymes act as viral restriction factors by mutating viral genomes. Mutation of the cellular genome is presumed to be an off-target activity of the enzymes, although the regulatory measures for APOBEC3 expression and activity remain undefined. It is therefore difficult to predict circumstances that enable APOBEC3 interaction with cellular DNA that leads to mutagenesis. The APOBEC3A (A3A) enzyme is the most potent deaminase of the family. Using proteomics, we evaluate protein interactors of A3A to identify potential regulators. We find that A3A interacts with the chaperonin-containing TCP-1 (CCT) complex, a cellular machine that assists in protein folding and function. Importantly, depletion of CCT results in A3A-induced DNA damage and cytotoxicity. Evaluation of cancer genomes demonstrates an enrichment of A3A mutational signatures in cancers with silencing mutations in CCT subunit genes. Together, these data suggest that the CCT complex interacts with A3A, and that disruption of CCT function results in increased A3A mutational activity.
Identifiants
pubmed: 34347354
doi: 10.15252/embr.202052145
pmc: PMC8419680
doi:
Substances chimiques
Proteins
0
APOBEC3A protein, human
EC 3.5.4.5
Cytidine Deaminase
EC 3.5.4.5
Chaperonin Containing TCP-1
EC 3.6.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e52145Subventions
Organisme : NCI NIH HHS
ID : R01 CA181359
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA185799
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118891
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA212299
Pays : United States
Informations de copyright
© 2021 The Authors.
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