The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability
Open accessAbstract
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.
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Cites
Genome engineering using the CRISPR-Cas9 system
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Self-citationMass-spectrometry-based draft of the human proteome
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Biallelic Inactivation of BRCA2 in Fanconi Anemia
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Cited by
R-Loops as Cellular Regulators and Genomic Threats
Crossley, M. P., Bocek, M., & Cimprich, K. A. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.024 · Cited by 746
Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells
Garaycoechea, J. I., Crossan, G. P., Langevin, F., Mulderrig, L., Louzada, S., Yang, F., Guilbaud, G., Park, N., Roerink, S., Nik-Zainal, S., et al. (2018) · Nature · doi:10.1038/nature25154 · Cited by 389
Potassium-modulated δ-MnO2 as robust catalysts for formaldehyde oxidation at room temperature
Ji, J., Lu, X., Chen, C., He, M., & Huang, H. (2020) · Applied Catalysis B: Environmental · doi:10.1016/j.apcatb.2019.118210 · Cited by 284
Genetically encoded formaldehyde sensors inspired by a protein intra-helical crosslinking reaction
Zhu, R., Zhang, G., Jing, M., Han, Y., Li, J., Zhao, J., Li, Y., & Chen, P. R. (2021) · Nature Communications · doi:10.1038/s41467-020-20754-4 · Cited by 49
Metadata
- Authors
- Tan, S. L. W., Chadha, S., Liu, Y., Gabasova, E., Perera, D., Ahmed, K., Constantinou, S., Renaudin, X., Lee, M., Aebersold, R., & Venkitaraman, A. R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 169
- Issue
- 6
- Pages
- 1105-1118.e15
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2621142869
- Cited by
- 209
- References
- 8
- FWCI
- 8.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Tan, S. L. W., Chadha, S., Liu, Y., Gabasova, E., Perera, D., Ahmed, K., Constantinou, S., Renaudin, X., Lee, M., Aebersold, R., & Venkitaraman, A. R. (2017). A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability. Cell. https://doi.org/10.1016/j.cell.2017.05.010
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