Dr. Nick Makridakis is an enthusiastic geneticist who not only helped me to pursue science systematically but also mentored me with valuable guidance for my scientific achievements. Throughout his research career his focus was on studying the role of mutations in the DNA polymerase activity (1, 2). I joined Nick’s lab as postdoctoral fellow and studied role of somatic mutations in prostate cancer in translesion synthesis (TLS) DNA polymerase such as POLK.
What TLS polymerases do?
DNA repair process is quick however sometimes these DNA damages remain un-repaired. TLS DNA polymerases bypass such damages and allow cells an additional time to repair the DNA damage. We identified mutations in DNA polymerase POLK in prostate cancer samples (PCa) by sanger sequencing and later systematically analyzed that those mutations were altering TLS activity (2). This study was a foundation that led us to investigate mutations in DNA repairome genes in prostate cancer.
Mutations in DNA repairome: We deep sequenced the exons of 124 genes involved in the DNA damage repair/response genes in 52 PCas and matched normal tissue samples (peripheral blood lymphocytes), at very high resolution (312–768 average read depth). We found 1433 somatic mutations in these tumors (24–38 mutations per patient, depending on race and Gleason score). We further found that all prostate tumors had somatic mutations in DNA repair/response genes, regardless of the Gleason score.
Do health disparities affect DNA damage?
Another major goal of this study was to examine the issue of health disparities in PCa. African have the highest incidence of PCa in the world. We found that part of this difference between African Americans and Caucasians may be due to the high heterogeneity in the somatic mutations of the DNA repairome.
Significance of the study: DNA repairome was somatically mutated in all prostate tumors that were tested. We further observed that the well-known difference in PCa incidence and mortality between African Americans and Caucasians may have a genetic basis, specifically involving the DNA repairome. Tumors in African Americans, compared with Caucasians, had distinct mutations in the DNA repairome. In our opinion after further validation, these data can be used to select important bio-markers of prostate cancer, mortality and racial disparities, and to guide therapeutic options.
Year 2019 my parents visit to US
Contribution of my family: My father inspired me to do hard work, my mother gave courage to follow my dream, brothers Rakesh Yadav & Mukesh Yadav are my hidden strength always there for me when I needed. My husband and my loving son Aarav have been supportive by giving me "me-time" for this study.
An CL, Chen D, Makridakis NM. Systematic biochemical analysis of somatic missense mutations in DNA polymerase beta found in prostate cancer reveal alteration of enzymatic function. Hum Mutat 2011; 32: 415-423.
Yadav S, Mukhopadhyay S, Anbalagan M, Makridakis N. Somatic Mutations in Catalytic Core of POLK Reported in Prostate Cancer Alter Translesion DNA Synthesis. Hum Mutat 2015; 36: 873-880