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Interaction with the CCT chaperonin complex limits cytotoxicity from the APOBEC3A cytosine deaminase.

ABSTRACT: The APOBEC3 cytosine 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 the 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 evaluated protein interactors of A3A to identify potential regulators. We found 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 resulted in increased A3A-induced cytotoxicity. Evaluation of cancer genomes demonstrated 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Katarzyna Kulej

LAB HEAD: Benjamin A. Garcia

PROVIDER: PXD024191 | Pride | 2021-07-02

REPOSITORIES: Pride

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Project description:International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not been identified by conventional epidemiology yet potentially make a substantial contribution to cancer burden1. This pertains to clear cell renal cell carcinoma (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence2. Some carcinogens generate somatic mutations and a complementary strategy for detecting past exposures is to sequence the genomes of cancers from populations with different incidence rates and infer underlying causes from differences in patterns of somatic mutations. Here, we sequenced 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in >70% cases and <2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher kidney cancer incidence rates (p-value <6 × 10−18). Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, geographically variable, mutagenic exposures potentially affecting 10s of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics. Linked cross omic data sets:Geographic variation of mutagenic exposures in kidney cancer genomes – patient metadata files (Mutographs) associated with this study are available in the European Genome-Phenome Archive: https://ega-archive.org/datasets/EGAD00001012223.

			Action	DRS
	A3A_1_.mzML	Mzml
	A3A_1_01.mzML	Mzml
	A3A_1_01.raw	Raw
	A3A_1_02.mzML	Mzml
	A3A_1_02.raw	Raw

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Interaction with the CCT chaperonin complex limits cytotoxicity from the APOBEC3A cytosine deaminase.

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