Genotoxic stresses that damage the chromosomal DNA or inhibit the progression of a DNA replication fork can lead to instability of the genetic information and hence cause cellular transformation. One key factor that both signals the presence of genotoxic stress and serves to minimize DNA damage is RPA, the eukaryotic single-stranded DNA-binding protein. A focus of our research is to understand the roles of RPA in enhancing genomic stability. A major line of investigation analyzes the functional significance of RPA phosphorylation by checkpoint (e.g., ATR, ATM) and cell-cycle (e.g., cyclin A-Cdk2) kinases under stress conditions. We have recently found that: 1) in interphase cells with DNA damage, RPA phosphorylation is required for efficient DNA repair by homologous recombination; 2) under conditions of DNA replication stress, RPA phosphorylation by ATR stimulates repair DNA synthesis and prevents ssDNA accumulation; and 3) in cells experiencing mitotic DNA damage, mitotic RPA hyper-phosphorylation facilitates release of cells from a damaged mitosis into a 2N G1 phase, thereby increasing cell viability. These studies indicate that the RPA phosphorylation state causes DNA lesions to be channeled into different DNA repair pathways. Ongoing work is establishing the repair and signaling factors regulated by the RPA phosphorylation state.
Professor, Department of Biochemistry and Molecular Pharmacology
Course Director, Introduction to Molecular Genetics
Director, Research Emergency Management and Enterprise Resilience
PhD from University of California, Los Angeles
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Blood. 2015 DEC 3; 126(23):?-?
Journal of cell biology. 2014 Aug 18; 206(4):493-507
FEBS journal. 2012 Feb; 279(3):370-383
International journal of biochemistry & cell biology. 2011 Sep; 43(9):1354-1364
Current opinion in cell biology. 2011 Jun; 23(3):284-292
Single molecule analysis demonstrates that RPA phosphorylation is necessary for efficient fork movement during replication stress [Meeting Abstract]
Molecular biology of the cell. 2010 Dec 15; 21(24):?-?
Nature structural & molecular biology. 2010 Mar; 17(3):365-372
Journal of cell science. 2009 Nov 15; 122(Pt 22):4070-4080