Journal article
A moving target for drug discovery: Structure activity relationship and many genome (de)stabilizing functions of the RAD52 protein
DNA repair, Vol.120, 103421
12/2022
DOI: 10.1016/j.dnarep.2022.103421
PMCID: PMC9888176
PMID: 36327799
Abstract
BRCA-ness phenotype, a signature of many breast and ovarian cancers, manifests as deficiency in homologous recombination, and as defects in protection and repair of damaged DNA replication forks. A dependence of such cancers on DNA repair factors less important for survival of BRCA-proficient cells, offers opportunities for development of novel chemotherapeutic interventions. The first drugs targeting BRCA-deficient cancers, poly-ADP-ribose polymerase (PARP) inhibitors have been approved for the treatment of advanced, chemotherapy resistant cancers in patients with BRCA1/2 germline mutations. Nine additional proteins that can be targeted to selectively kill BRCA-deficient cancer cells have been identified. Among them, a DNA repair protein RAD52 is an especially attractive target due to general tolerance of the RAD52 loss of function, and protective role of an inactivating mutation. Yet, the effective pharmacological inhibitors of RAD52 have not been forthcoming. In this review, we discuss advances in the state of our knowledge of the RAD52 structure, activities and cellular functions, with a specific focus on the features that make RAD52 an attractive, but difficult drug target.
•RAD52 DNA repair protein is important for survival of BRCA-deficient cancers.•RAD52 is a coveted target for development of small-molecule inhibitors.•Multiple cellular functions of RAD52 are enabled by its interactions with DNA and RNA.•Incomplete structure activity relationship for RAD52 complicates its targeting.
Details
- Title: Subtitle
- A moving target for drug discovery: Structure activity relationship and many genome (de)stabilizing functions of the RAD52 protein
- Creators
- Divya S. Bhat - Roy J. and Lucille A. Carver College of MedicineM. Ashley Spies - University of IowaMaria Spies - Department of Biochemistry, University of Iowa Carver College of Medicine, 51 Newton Road, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- DNA repair, Vol.120, 103421
- DOI
- 10.1016/j.dnarep.2022.103421
- PMID
- 36327799
- PMCID
- PMC9888176
- NLM abbreviation
- DNA Repair (Amst)
- ISSN
- 1568-7864
- eISSN
- 1568-7856
- Publisher
- Elsevier B.V
- Language
- English
- Date published
- 12/2022
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Biochemistry and Molecular Biology; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984311559602771
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