Dr. Steven RobertsAssistant professor
WSU School of Molecular Biosciences
Title: Editing of Cancer Genomes by APOBEC cytidine deaminases
April 20th: 1 pm EST, 12 pm CST, 10 am PST
Research & Interests
Mutations and chromosomal rearrangements underlie a variety of diseases from autism to cancer. What causes these genetic alterations, however, is frequently unclear. Recent large scale re-sequencing of human tumor genomes has revealed that cancer is a complex set of diseases, with tumors displaying different clinical and cellular characteristics. Along with these phenotypic differences, tumors have varying mutation frequencies and mutagenic processes occurring that ultimately impact aspects of disease onset, progression, and ultimately drug resistance. The focus of my lab is to understand the plasticity of genomes and how such alteration contributes to each of these aspects of carcinogenesis. We use biochemical, genetic, and genomic approaches to probe these questions.
One specific aspect of my research concerns the mutagenic nature of lesions in single-stranded (ss) DNA. Lesions that occur in single-stranded DNA are difficult to remove by traditional DNA excision repair pathways since these processes require the use of the complementary DNA strand. Using yeast as a model organism, my research has determined that ssDNA intermediates formed during normal DNA transactions like DNA double strand break repair and DNA replication are prone to base damage. Failure to accurately remove these lesions can lead to the formation of "mutation clusters." Lesions in ssDNA are also a frequent cause of mutations in human cancers. By analyzing mutations occurring across the genome of re-sequenced tumors, I have found that the APOBEC family of cytidine deaminases deaminate cytidine in ssDNA leading to increased mutation frequencies in specific tumor types. My research addresses how lesions in ssDNA are processed, what types of genetic alterations they induce, and how endogenous APOBEC activity is unleashed during cancer progression. Ultimately we are interested in how these processes contribute to cancer and whether they can be prevented to mitigate disease.
Sakofsky, C.J., Roberts, S.A., Malc, E., Mieczkowski, P.A., Resnick, M.A., Gordenin, D.A, and Malkova, A. (2014) Break-Induced Replication Is a Source of Mutation Clusters Underlying Kataegis. Cell Reports, (7) published online May 28, 2014. PMID:24882007
Roberts, S.A., Lawrence, M.S., Klimczak, L.J., Grimm, S.A., Fargo, D., Stojanov, P., Kiezun, A., Kryukov, G.V., Carter, S.L., Saksena, G., Harris, S., Shah, R.R., Resnick, M.A., Getz, G., and Gordenin, D.A. (2013) An APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers. Nature Genetics. 45(9):970-6. doi:10.1038/ng.2702. PMID: 23852170
Roberts, S.A., Sterling, J, Thompson, C, Harris, S, Mav, D, Shah, R, Klimczak, L.J., Kryukov, G.V., Malc, E, Mieczkowski, P.A., Resnick, M.A., and Gordenin, D.A. (2012) Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-Strand DNA Regions. Molecular Cell. 46(4):424-35. PMCID: PMC3361558
Roberts S.A., Strande N., Burkhalter M.D., Strom C., Havener J.M., Hasty P., and Ramsden D.A. (2010). Ku is a 5'-dRP/AP lyase that excises nucleotide damage near broken ends. Nature. 464(7292):1214-7. PMCID: PMC2859099
Roberts, S.A., and Ramsden, D.A. (2007). Binding of the Non-Homologous End Joining Factor, Ku, to protein-occluded ends. Journal of Biological Chemistry. 282(14): 10605-13. PMID: 17289670
Strande, Natasha., Carvajal-Garcia, J., Hallett, R., Waters, C, Roberts, S.A., Strom, C., Kuhlman, B., and Ramsden, D.A. (2014) Requirements for 5’dRP/AP lyase activity in Ku. Nucleic Acids Research. Accepted Aug. 21, 2014.
The Cancer Genome Atlas Research Network (2014) The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. accepted July 17, 2014.
The Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial carcinoma of the bladder. Nature. 20;507(7492):315-22. doi: 10.1038/nature12965. PMID:24476821
Lawrence, M.S., Stojanov, P., Polak, P., Kryukov, G.V., Cibulskis, K., Sivachenko, A., Carter, S.L., Stewart, C., Mermel, C.H., Roberts, S.A., Kiezun, A., Hammerman, P.S., McKenna, A., Drier, Y., Zou, L., Ramos, A.H., Pugh, T.J., Stransky, N., Helman, E., Kim, J., Sougnez, C., Ambrogio, L., Nickerson, E., Shefler, E., Cortés, M.L., Auclair, D., Saksena, G., Voet, D., Noble, M., DiCara, D., Lin, P., Lichtenstein, L., Heiman, D.I., Fennell, T., Imielinski, M., Hernandez, B., Hodis, E., Baca, S., Dulak, A.M., Lohr, J., Landau, D., Wu, C.J., Melendez-Zajgla, J., Hidalgo-Miranda, A., Koren, A., McCarroll, S.A., Mora, J., Crompton, B., Onofrio, R., Parkin, M., Winckler, W., Ardlie, K., Gabriel, S.B., Roberts, C.W.M., Biegel, J.A., Stegmaier, K., Bass, A.J., Garraway, L.A., Meyerson, M., Golub, T.R., Gordenin, D.A., Sunyaev, S., Lander, E.S., Getz, G. (2013) Mutational heterogeneity in cancer and the search for new cancer genes. Nature. 499(7457):214-8. PMID: 23770567
Chan, K., Sterling, J.F., Roberts, S.A., Bhagwat, A.S., Resnick, M.A., and Gordenin, D.A. (2012) Base damage within single-strand DNA underlies in vivo hypermutability induced by a ubiquitous environmental agent. PLoS Genetics. 8(12):e1003149. PMID: 23271983
Strande, N., Roberts, S.A., Oh, S., Hendrickson, E.A., and Ramsden, D.A. (2012) Specificity of Ku’s 5'dRP/AP lyase promotes Nonhomologous end joining (NHEJ) fidelity at damaged ends. Journal of Biological Chemistry. 287(17):13686-93. PMCID: PMC3340204
Burch L.H., Yang, Y., Sterling J.F., Roberts S.A., Chao F.G., Xu H., Zhang L., Walsh J., Resnick M.A., Mieczkowski P.A., and Gordenin D.A., (2011) Damage-induced localized hypermutability. Cell Cycle. Apr 1;10(7):1073-85. PMCID: PMC3100884
Burkhalter M.D., Roberts S.A., Havener J.M., and Ramsden D.A. (2009) Availability of nucleotides helps determine how cells repair double strand breaks. DNA Repair (Amst). 8(11):1258-63. PMCID: PMC2763971
Roberts, Steven A. and Gordenin, Dmitry A. (2014) Clustered Mutations in Human Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net/. Published online Jan. 14. doi: 10.1002/9780470015902.a0024941
Roberts, Steven A. and Gordenin, Dmitry A. (2014) Clustered and genome-wide transient mutagenesis in human cancers: Hypermutation without permanent mutators or loss of fitness. BioEssays. 2014 Feb 26. doi: 10.1002/bies.201300140. PMID:24615916