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Principal Investigator: Kara A Bernstein
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $451,972
Funding agency: National Institute of Environmental Health Sciences
Project Summary/Abstract:
Accurate repair of DNA damage is critical for genetic stability, and for preventing aging-related degeneration
and cancer. We are working to identify key factors that regulate accurate repair of DNA double-strand breaks
(DSBs) through the error-free homologous recombination (HR) pathway. DSBs can arise from many sources
including endogenous replication fork damage, exogenous environmental toxicants, or oxidative stresses
induced by endogenous sources and during pro-inflammatory responses to toxicant injury. We found that the
RAD51 paralogs are critical for promoting HR and hence for suppressing error-prone repair mechanisms. Over
300 studies link mutations in human RAD51 paralogs with cancer, and women with breast or ovarian cancer
are now screened for RAD51 paralog mutations. However, it remains largely unknown which RAD51 paralog
mutations are pathogenic and how these mutations sensitize individuals to environmentally induced-DNA
damage due to our lack of functional analysis of either the wild-type or mutated proteins. We do not know how
these proteins are recruited, their functional components, or the disruptions caused by mutations or
polymorphisms in the RAD51 paralogs. This knowledge gap results from low abundance of endogenous
RAD51 paralog proteins, insolubility of the recombinant proteins, as well as embryonic lethality in knock-out
mice. We are therefore using genetic, biochemical, and cell biological approaches to characterize RAD51
paralog function upon exposure to DSB inducing agents. We will use ionizing radiation (IR) and bleomycin as
model agents for environmentally relevant DSB-inducing agents. Using complementary approaches in
combination with high-throughput genetic screening, we are now uniquely poised to address how RAD51
paralog mutations predispose individuals to human cancer and thus, to identify opportunities for determining
who is at risk for cancer development upon exposure to environmental carcinogens. Our ultimate goal is to
enable development of precision medicine strategies for individual patients whose tumors harbor a RAD51
paralog mutation profile.
Terms: <ATP phosphohydrolase><ATPase><Aberrant Chromosome><Address><Adenosine Triphosphatase><Assay><BRCA 1/2><BRCA1/2><BRCA2><BRCA2 gene><Bioassay><Biochemical><Biological><Biological Assay><Biological Markers><Bleo><Bleomycin><Breast Cancer><Breast Cancer 2 Gene><Breast Cancer Type 2 Susceptibility Gene><Breast Neoplasms><Breast Tumors><CRISPR><CRISPR/Cas system><Cancers><Cell Body><Cells><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome abnormality><Classification><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Co-Immunoprecipitations><Complex><Cytogenetic Aberrations><Cytogenetic Abnormalities><DNA Damage><DNA Damage Repair><DNA Double Strand Break><DNA Injury><DNA Repair><DNA Repair Pathway><DNA Repair Protein XRCC2><DNA replication fork><DNA-Protein Interaction><Development><Double Strand Break Repair><Dysfunction><Early Onset Gene Breast Cancer 2><Embryo><Embryonic><Environment><Environmental Carcinogens><Environmental Exposure><Environmental Toxin><Environmental genotoxicant><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Exposure to><FANCD1><Familial Breast and Ovarian Cancer Syndrome><Filament><Functional disorder><Genetic><Genetic Alteration><Genetic Change><Genetic Polymorphism><Genetic Screening><Genetic defect><Genome Instability><Genomic Instability><Germ-Line Mutation><Germline Mutation><Goals><Hereditary><Hereditary Breast Cancer 2><Hereditary Breast and Ovarian Cancer><Hereditary Breast and Ovarian Cancer Syndrome><Hereditary Mutation><High Throughput Assay><Human><Human Cell Line><Hybrids><Individual><Inflammatory Response><Inherited><Injury><Invaded><Ionizing Electromagnetic Radiation><Ionizing radiation><KO mice><Knock-in><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Link><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Mammary Cancer><Mammary Neoplasms><Measures><Mediating><Metaphase><Methods><Mice><Mice Mammals><Microscopy><Mitotic Metaphase><Modeling><Modern Man><Molecular><Murine><Mus><Mutate><Mutation><NGS Method><NGS system><Null Mouse><Ovarian Tumor><Ovary Cancer><Ovary Neoplasms><Ovary Tumor><Oxidative Stress Induction><PALB2><PALB2 gene><Pathogenicity><Pathway interactions><Physiopathology><Proteins><RAD51C><RAD51C gene><Radiation-Ionizing Total><Recombinant Proteins><Reporter><Role><Screening for Ovarian Cancer><Source><System><Systematics><Technology><Testing><Therapeutic><Time><Toxic Environmental Agents><Toxic Environmental Substances><Tracer><Unscheduled DNA Synthesis><Variant><Variation><Visualization><Walker-A Motif><Woman><Work><X-Ray Repair Cross Complementing Protein 2><X-Ray Repair Cross Complementing Protein 3><X-Ray Repair, Comlementing Defective, In Chinese Hamster, 3><XRCC2><XRCC2 gene><XRCC3><XRCC3 gene><Yeasts><aging associated><aging related><bio-markers><biologic><biologic marker><biomarker><brca 2 gene><brca gene><cancer cell genome><cancer genome><cancer predisposition><cancer risk><chromosomal defect><chromosome defect><cost effective><developmental><environmental mutagenesis><environmental mutagens><environmental toxicant><epidemiologic investigation><epidemiology study><experiment><experimental research><experimental study><experiments><gene repair><genome integrity><genome mutation><genomic integrity><germ-line defect><germline variant><high throughput screening><homologous recombination><homologous recombination deficiency><homologous recombination repair deficiency><in vivo><individual patient><injuries><ionizing output><knockin><malignancy><malignant breast tumor><mammary tumor><member><mutant><neoplasm/cancer><next gen sequencing><next generation sequencing><nextgen sequencing><novel><ovarian cancer><ovarian cancer detection><ovarian cancer early detection><ovarian cancer early screening><ovarian neoplasm><oxidative damage><oxidative injury><paralog><paralogous gene><partner and localizer of BRCA2><pathophysiology><pathway><polymorphism><precision medicine><precision-based medicine><prevent><preventing><protein protein interaction><recruit><repair><repaired><replication fork><screening panel><social role><toxicant><tumor><tumor genome><unclassified variant><variant of uncertain clinical significance><variant of uncertain significance><variant of undetermined significance><variant of unknown significance>