Department of Biochemistry and Molecular Biology

Biography:
Recipient of Merit Awards from the National Cancer Institute (NCI) from 1993 to 2003 and from 2002 to 2011.  Recipient of the Distinguished Faculty Research Award from the Graduate School of Biomedical Sciences at the University of Texas Medical Branch in 2004.  Recipient of the Environmental Mutagen Society Award for Many Years of Outstanding Research into the Mechanics of DNA Repair and Mutagenesis in Eukaryotic Cells in 2005. Elected Fellow of the American Association for the Advancement of Science in 2005, and Fellow in the American Academy of Microbiology in 2009.

Research Interests:
The S. Prakash laboratory concentrates on the study of DNA replication and DNA repair in yeast and in humans. The Prakash laboratory has made pioneering contributions to the understanding of DNA repair mechanisms that include nucleotide excision repair, base excision repair and mismatch repair.  Their studies led to the discovery of translesion synthesis DNA polymerases and to the elucidation of their roles in replication of damaged DNA and they have contributed to the determination of the roles of DNA polymerase delta and DNA polymerase epsilon in replication.

Mechanisms of replication through DNA lesions
DNA lesions in the template strand block the progression of the replication fork due to inhibition of DNA synthesis by the replicative polymerase (Pol).  Studies from the Prakash group identified the first DNA polymerase (Pol eta) which could efficiently replicate through the  UV induced covalently-linked cyclobutane pyrimidine dimers, and in subsequent studies, they showed that mutations in Pol eta cause the cancer prone syndrome, xeroderma pigmentosum variant (XPV).  A combination of genetic, cellular, biochemical, and structural studies carried out by the Prakash group have led to the following deductions: (a) the active sites of translesion synthesis (TLS) DNA polymerases are uniquely adapted to replicate through different types of DNA lesions;  (b) the catalytic efficiency and fidelity of TLS Pols are actively modulated by post-translational mechanisms and by protein-protein interactions; (c) TLS occurs in conjunction with the replication fork stalled at the lesion site, and (d) TLS mechanisms provide a key safeguard against genome instability and tumorigenesis.  The ongoing studies are aimed at defining the mechanisms that underlie these various aspects of the TLS process.

DNA repair and cancer
DNA repair processes and TLS mechanisms prevent genome instability and protect against tumorigenesis in normal cells; however, ongoing studies in the Prakash group have revealed that DNA repair and related processes become deranged and error-prone in cancer cells.  They are examining the impact of these error-prone repair mechanisms on cancer evolution and carrying out studies to determine whether targeting of proteins in these error-prone DNA repair pathways could be utilized for cancer therapeutics.