Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing
Open accessAbstract
Mutations that cause chromosome instability (CIN) in cancer cells produce “sublethal” deficiencies in an essential process (chromosome segregation) and, therefore, may represent a major untapped resource that could be exploited for therapeutic benefit in the treatment of cancer. If second-site unlinked genes can be identified, that when knocked down, cause a synthetic lethal (SL) phenotype in combination with a somatic mutation in a CIN gene, novel candidate therapeutic targets will be identified. To test this idea, we took a cross species SL candidate gene approach by recapitulating a SL interaction observed between rad54 and rad27 mutations in yeast, via knockdown of the highly sequence- and functionally-related proteins RAD54B and FEN1 in a cancer cell line. We show that knockdown of RAD54B, a gene known to be somatically mutated in cancer, causes CIN in mammalian cells. Using high-content microscopy techniques, we demonstrate that RAD54B-deficient human colorectal cancer cells are sensitive to SL killing by reduced FEN1 expression, while isogenic RAD54B proficient cells are not. This conserved SL interaction suggests that extrapolating SL interactions observed in model organisms for homologous genes mutated in human cancers will aid in the identification of novel therapeutic targets for specific killing of cancerous cells exhibiting CIN.
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Conservation of genetic interactions from yeast to human cells has been observed, particularly within fundamental bioprocesses like DNA synthesis and repair and chromosome segregation.
“conservation of genetic interactions from yeast to human cells has been observed (51, 52), particularly within fundamental bioprocesses like DNA synthesis and repair and chromosome segregation”
From A global genetic interaction network maps a wiring diagram of cellular function (2016) · cites this paper as [52]
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A global genetic interaction network maps a wiring diagram of cellular function
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Self-citationA Comparative Genomic Approach for Identifying Synthetic Lethal Interactions in Human Cancer
Deshpande, R., Asiedu, M. K., Klebig, M., Sutor, S., Kuzmin, E., Nelson, J., Piotrowski, J., Ho Shin, S., Yoshida, M., Costanzo, M., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3956 · Cited by 64 · see citing works
- Authors
- McManus, K. J., Barrett, I. J., Nouhi, Y., & Hieter, P.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Hieter, Philip
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-03
- Volume
- 106
- Issue
- 9
- Pages
- 3276-3281
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2651317
- OpenAlex
- W2003438913
- Cited by
- 133
- References
- 49
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 4 · 2018: 10 · 2017: 10 · 2016: 9 · 2015: 6 · 2014: 11 · 2013: 13 · 2012: 10
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Michael Smith Health Research BC
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- synthetic lethality, RAD54B, FEN1, chromosomal instability, colorectal cancer, gene silencing, chromosome segregation, therapeutic target, Rad54, Rad27, tumor cell killing
- MeSH terms
- DNA Helicases, Humans, Nuclear Proteins, Phenotype, Substrate Specificity, Colorectal Neoplasms, Apoptosis, Gene Silencing, Chromosomal Instability, Flap Endonucleases, Tissue Culture Techniques
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