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

Abstract	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, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde. Acetaldehyde, an alcohol catabolite detoxified by ALDH2, precipitates similar effects. Ribonuclease H1 ameliorates replication fork instability and chromosomal aberrations provoked by aldehyde-induced BRCA2 haploinsufficiency, suggesting that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA-DNA hybrids (R-loops). These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health.
Authors	Shawn Lu Wen Tan, Saakshi Chadha, Yansheng Liu, Evelina Gabasova, David Perera, Karim Ahmed, Stephanie Constantinou, Xavier Renaudin, MiYoung Lee, Ruedi Aebersold, Ashok R Venkitaraman
Journal	Cell (Cell) Vol. 169 Issue 6 Pg. 1105-1118.e15 (Jun 01 2017) ISSN: 1097-4172 [Electronic] United States
PMID	28575672 (Publication Type: Journal Article)
Copyright	Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Chemical References	BRCA2 Protein BRCA2 protein, human DNA-Binding Proteins MRE11 protein, human Proteome Toxins, Biological Formaldehyde MRE11 Homologue Protein Ribonuclease H ribonuclease HI
Topics	BRCA2 Protein (genetics) Chromosome Aberrations (drug effects) DNA Damage DNA Replication (drug effects) DNA-Binding Proteins (metabolism) Formaldehyde (toxicity) Genomic Instability (drug effects) Haploinsufficiency HeLa Cells Humans MRE11 Homologue Protein Proteome Ribonuclease H (metabolism) Toxins, Biological (toxicity)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!