1. The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target.
- Author
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Sharp MF, Bythell-Douglas R, Deans AJ, and Crismani W
- Subjects
- Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins deficiency, BRCA1 Protein deficiency, BRCA2 Protein deficiency, DNA Damage, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors therapeutic use, Fanconi Anemia genetics, Fanconi Anemia metabolism, Fanconi Anemia pathology, Fanconi Anemia Complementation Group Proteins antagonists & inhibitors, Fanconi Anemia Complementation Group Proteins metabolism, Gene Expression Regulation, Neoplastic, Humans, Molecular Targeted Therapy methods, Morpholines therapeutic use, Pyrones therapeutic use, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Synthetic Lethal Mutations, Ubiquitin-Protein Ligases antagonists & inhibitors, Ubiquitin-Protein Ligases metabolism, Ubiquitins antagonists & inhibitors, Ubiquitins genetics, Ubiquitins metabolism, Ataxia Telangiectasia Mutated Proteins genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, DNA Repair drug effects, Fanconi Anemia drug therapy, Fanconi Anemia Complementation Group Proteins genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical-and likely singular-role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous DNA damage, including cells that lack BRCA1, BRCA2, ATM, or functionally related genes. In this perspective, we discuss the genetic and biochemical evidence in support of the FA core complex as a compelling drug target for cancer therapy. In particular, we discuss the genetic, biochemical, and structural data that could rapidly advance our capacity to identify and implement the use of FA core complex inhibitors in the clinic., Competing Interests: Declaration of interests A.J.D. receives sponsored research support from Tessellate Bioscience for projects related to this manuscript., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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