| Laboratory of Molecular Gerontology |
Intramural Program Investigators ^ Home ^ |
| Robert M. Brosh, Jr., Ph.D., Senior Investigator Section on DNA Helicases |
 Dr. Robert Brosh received his M.S. in biochemistry from Texas A & M University in 1988 and his Ph.D. in biology from the University of North Carolina at Chapel Hill in 1996. He did postdoctoral work at NIH before assuming his present position in the Laboratory of Molecular Genetics, NIA.Research Interests: Roles of DNA Helicases in Genomic Stability: The growing number of DNA helicases implicated in human disease suggests that these enzymes have vital specialized roles during replication, DNA repair, recombination, and transcription. We and others have shown that both Werner (WRN) and Bloom (BLM) gene products are helicases, suggesting that basic defects in DNA metabolic pathways give rise to the aberrant cellular and clinical phenotypes of the premature aging disorder Werner Syndrome (WS) and cancer predisposition disorder Bloom Syndrome (BS). Cellular studies and biochemical data are consistent with this notion; however, the precise molecular functions of the sequence-related WRN and BLM proteins remain to be defined. Defining the biochemical functions of DNA helicases will help us to understand molecular defects associated with aging and cancer. |
| Helicases as Caretakers of the Genome: The defects observed in WS and BS cells may result from the inability to resolve alternate DNA structures. DNA structures such as hairpins, triplexes, or tetraplexes may deter replication or repair and contribute to genome instability. One hypothesis is that WRN or BLM helicases may function to resolve structures that impede progression of the replication fork. Replication defects observed in WS and BS cells are consistent with this notion. Recently we have shown that WRN and BLM enzymes unwind a DNA triple helix. Since triplex structures are known to be recombinogenic, it is reasonable to suggest that triplex structures might be more persistent in WS and BS cells, and could contribute to the genomic instability characteristic of both syndromes. Our current studies address the catalytic activities of WRN and BLM helicases on other types of novel DNA structures that may arise during replication or repair. |
| Protein Interactions of WRN and BLM Helicases: To understand the molecular functions of DNA helicases, we are interested in protein interactions of WRN and BLM. Defining the protein interactions of WRN and BLM helicases will help to elucidate cellular processes to prevent chromosome breaks or correct DNA damage in order to maintain genome integrity. We demonstrated the first physical and functional interactions of WRN and BLM helicases with the single stranded DNA binding protein Replication Protein A (RPA). The presence of RPA stimulates the helicases to unwind long DNA duplexes, an activity that may be important in replication or some other pathway of DNA metabolism. Ongoing studies in this area explore other protein interactions of WRN and BLM that are important to genome stability. |
| Contact Information: Laboratory of Molecular Gerontology Biomedical Research Center, room 06B125 251 Bayview Boulevard, Suite 100 Baltimore, MD 21224-6825 Phone 410-558-8578 Fax 410-558-8157 E mail broshr@grc.nia.nih.gov For more information about the Laboratory: http://www.grc.nia.nih.gov/branches/lmg/lmg.htm |
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