Abstract
SummaryMutations 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.
Highlights
Inherited germline mutations affecting a single copy of the BRCA2 tumor suppressor gene predispose to cancers of the breast, ovaries, pancreas, prostate, and other organs (Breast Cancer Linkage Consortium, 1999)
Replication, HeLa Kyoto cells exposed to formaldehyde for 2 hr were labeled with 5-ethynyl 20-deoxyuridine (EdU) to measure DNA synthesis and co-stained for the S-phase marker, proliferating cell nuclear antigen (PCNA)
PCNA-positive cells exhibit a dose-dependent decrease in EdU incorporation when exposed to 100 mM or 300 mM formaldehyde (Figure 1A)
Summary
Inherited germline mutations affecting a single copy of the BRCA2 tumor suppressor gene predispose to cancers of the breast, ovaries, pancreas, prostate, and other organs (Breast Cancer Linkage Consortium, 1999). The most prevalent BRCA2 alleles that confer a clinically significant risk of cancer susceptibility encode nonsense or frameshift mutations, which prematurely truncate the BRCA2 protein (Rebbeck et al, 2015) (Breast Cancer Information Core [BIC] database, https://research.nhgri.nih.gov/bic/). These truncating mutations include the 6174delT mutation prevalent among the Ashkenazim (Neuhausen et al, 1996), the pathogenic truncation 3036del (BIC database) representative of variants associated with breast and ovarian cancer, or carboxyl (C)-terminal truncating mutations like 7691insAT or 9900insA implicated in Fanconi anemia (Howlett et al, 2002). We have investigated the mechanism by which heterozygosity for such BRCA2 truncating mutations may promote carcinogenesis
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