Dataset Information

Aldehyde exposure unmasks genome instability in cells heterozygous for clinically relevant BRCA2 mutations

ABSTRACT: Abnormalities provoked in human cells heterozygous for clinically relevant truncating mutations in BRCA2 by their exposure to naturally occurring aldehydes define a mechanism promoting carcinogenesis in mutation carriers. The ubiquitous metabolite and environmental toxin, formaldehyde, triggers replication fork instability and structural chromosomal aberrations in BRCA2 heterozygous cells. These abnormalities arise from a previously unrecognized effect of formaldehyde to selectively induce the proteasomal degradation of BRCA2, inducing functional haploinsufficiency only in cells where BRCA2 expression is already compromised by a heterozygous mutation. Similar effects are observed with acetaldehyde, a toxic product of alcohol catabolism. Replication fork instability and chromosomal aberrations in aldehyde-exposed cells arise from the unscheduled accumulation of RNA-DNA hybrids, revealing a mechanism driving genomic instability in BRCA2 heterozygous cells. We propose a model for cancer pathogenesis in which aldehyde exposure unmasks the carcinogenic potential of heterozygous BRCA2 mutations, with public health implications in mutation carriers.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Cervix Carcinoma

SUBMITTER: Yansheng Liu

LAB HEAD: Ruedi Aebersold

PROVIDER: PXD006106 | Pride | 2017-06-02

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	E1702271600_feature_alignment_requant.tsv.gz	Tabular
	SampleInfo_10vs10_201703.txt	Txt
	muelleto_M1512_163.raw	Raw
	txt.zip	Other
	yanliu_J150216_001.wiff	Wiff

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Publications

A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability.

Tan Shawn Lu Wen SLW Chadha Saakshi S Liu Yansheng Y Gabasova Evelina E Perera David D Ahmed Karim K Constantinou Stephanie S Renaudin Xavier X Lee MiYoung M Aebersold Ruedi R Venkitaraman Ashok R AR

Cell 20170601 6

Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, b ...[more]

PMID: 28575672

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