|Department:||School of Molecular Biosciences|
|Office:||Biotechnology/Life Sciences 335|
|Mailing Address:||PO Box 647520|
Pullman, WA 99164-7520
Genetic alterations-mutations and chromosomal rearrangements
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.
Hoopes JI, Hughes AL, Hobson LA, Cortez LM, Brown AJ, and Roberts SA* (2017) Avoidance of APOBEC3B-induced mutation by error-free lesion bypass. Nucleic Acids Research. 45(9):5243-5254. doi: 10.1093/nar/gkx169. PubMed PMID: 28334887. *Corresponding author.
Saini A, Roberts SA, Sterling JF, Malc EP, Mieczkowski PA, and Gordenin DA (2017) APOBEC3B cytidine deaminase targets the non-transcribed strand of tRNA genes in yeast. DNA Repair. 53:4-14. doi: 10.1016/j.dnarep.2017.03.003. Epub 2017 Mar 21. PubMed PMID: 28351647.
The Cancer Genome Atlas Research Network (2017) Integrated molecular characterization of invasive cervical cancer. Nature. 543:378-384. doi:10.1038/nature21386.
Saini N, Roberts SA, Klimczak LJ, Chan K, Grimm SA, Dai S, Fargo DC, Boyer JC, Kaufmann WK, Taylor JA, Lee E, Cortes-Ciriano I, Park PJ, Schurman SH, Malc EP, Mieczkowski PA, and Gordenin DA (2016) The impact of environmental and endogenous damage on human somatic mutation load. PLoS Genetics. 12(10):e1006385. doi: 10.1371/journal.pgen.1006385. PMID:27788131
Mao P, Smerdon MJ, Roberts SA, and Wyrick JJ (2016) Chromosomal Landscape of UV Damage Formation and Repair at Single Nucleotide Resolution. PNAS. 113(32):9057-62. doi: 10.1073/pnas.1606667113. Epub 2016 Jul 25.
Wyatt DW, Feng W, Conlin MP, Yousefzadeh MJ, Roberts SA, Mieczkowski P, Wood RD, Gupta GP, and Ramsden DA (2016) Essential roles for Polymerase q mediated end-joining in repair of chromosome breaks. Molecular Cell. 63(4):662-673. doi:http://dx.doi.org/10.1016/j.molcel.2016.06.020.
Hoopes JI, Cortez LM, Mertz TM, Malc EP, Mieczkowski PA, and Roberts SA* (2016) APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication. Cell Reports. 14(6):1273-82. PMID:26832400. *Corresponding author.
Kazanov MD, Roberts SA, Polak P, Stamatoyannopoulos J, Klimczak LJ, Gordenin DA, Sunyaev SR (2015) APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions. Cell Reports. 13(6):1103-9. doi: 10.1016/j.celrep.2015.09.077. Epub 2015 Oct 29. PMID: 26527001
Chan K, Roberts SA, Klimczak LJ, Sterling JF, Saini N, Malc EP, Kim J, Kwiatkowski DJ, Fargo D, Mieczkowski PA, Getz G, and Gordenin DA, (2015) An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nature Genetics. 47(9):1067-72. doi: 10.1038/ng.3378. Epub 2015 Aug 10. PMID: 26258849
Sakofsky CJ*, Roberts SA*, Malc E, Mieczkowski PA, Resnick MA, Gordenin DA, Malkova A. (2014) Break-induced replication is a source of mutation clusters underlying kataegis. Cell Rep. 7(5), 1640-8 . *Co-first author.
Strande N, Carvajal-Garcia J, Hallett R, Waters C, Roberts SA, Strom C, Kuhlman B, and Ramsden DA (2014) Requirements for 5’dRP/AP lyase activity in Ku. Nucleic Acids Research. 42(17):11136-43. PMID: 25200085
The Cancer Genome Atlas Research Network (2014) The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. 26(3):319-30. PMCID: PMC4160352
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 MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau D, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer genes. Nature. 499(7457):214-8. PMID: 23770567
Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, Kiezun A, Kryukov GV, Carter SL, Saksena G, Harris S, Shah RR, Resnick MA, Getz G, Gordenin DA. (2013) An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genetics. 45(9), 970-6
Roberts SA, Sterling J, Thompson C, Harris S, Mav D, Shah R, Klimczak LJ, Kryukov GV, Malc E, Mieczkowski PA, Resnick MA, Gordenin DA (2012) Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-Strand DNA Regions. Molecular Cell. 46(4), 424-35