We are interested in the molecular mechanisms that insure genome stability, and how these modulate cancer or disease risk and the response to therapy. We also develop genome engineering tools to treat or prevent disease, and to determine the functional phenotype of human mutations.
Genetic stability research: This work is focused on the human RECQ helicases that play key roles in DNA metabolism. Loss of function of three RECQ proteins, WRN, BLM and RECQ4, cause the heritable genetic instability/cancer predisposition diseases Werner, Bloom and Rothmund-Thomson syndromes respectively. Loss or aberrant expression of several of these proteins may also be common in adult cancers, and may modulate the response to chemotherapy. Our research is focused on in vivo functions and functional redundancy of the human RECQ helicases, and the roles of RECQ expression variation or loss in disease risk and the response to therapy.
Genome engineering: We were among the pioneers that have developed and used highly site-specific homing endonuclease proteins (HEGs or meganucleases) for genome engineering and DSB repair analyses. Current work uses engineered homing endonucleases and TALENs to target and correct disease-causing mutations in patient-derived iPS cells and to engineer Anopheles mosquitoes to prevent malaria transmission.
Functional phenotyping: Expertise and new tools from the above two project areas are being used to systematically capture, predict and then experimentally verify the functional consequences of mutations identified in DNA damage response and repair proteins as part of human genetic diversity and cancer genome projects.
More information? More detail can be found on our lab website - follow the link from this page.
Sidorova JM, Kehrli K, Mao F, Monnat RJ Jr. (2012) Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling. DNA Repair Dec 17. pii: S1568-7864(12)00284-4. doi: 10.1016/j.dnarep.2012.11.005. [Epub ahead of print].
Berti, M, Chaudhuri, AR, Thangavel, S, Gomathinayagam S, Kenig, S, Vujanovic, M., Odreman, F., Glatter, T., Graziano, S., Mendoza-Maldonado, R. Marino, F., Lucic, B., Biasin, V., Gstaiger, M., Aebersold, R., Sidorova, J.M., Monnat, RJ Jr., Lopes, M. and Vindigni, A. (2012) Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nature Structural and Molecular Biology (in press)
Lauper, J.L. Krause, A., Vaughan, T.L. and Monnat, R.J.,Jr. (2012) Spectrum and risk of neolpasia in Werner syndrome: a systematic review. PLoS ONE (in press)
Duxin JP, Moore HR, Sidorova J. Karanja, K, Honaker Y, Dao B, Piwnica-Worms H, Campbell JL, Monnat RJ Jr, Stewart SA (2012) An Okazaki fragment processing-independent role for human Dna2 during DNA replication. J. Biol. Chem. 287(26):21980-91.
Li H, Ulge UY, Hovde BT, Doyle LA, Monnat RJ Jr. (2012) Comprehensive homing endonuclease target site specificity profiling reveals evolutionary constraints and enables genome engineering applications. Nucleic Acids Res.40(6):2587-98.
Windbichler, N. Menichelli, M., Papathanos, P.A., Thyme, S.B., Li, H., Ulge, U.Y. Hovde, B.T., Baker, D., Monnat, R.J., Jr., Burt, A. and Crisanti, A. (2010)A synthetic, homing ednouclease-based genetic drive system in the human malaria mosquito. Nature 473(7346):212-5.
Bhavan-Thangavel, S., Mendoza-Maldonado, R. Tissino, E. Sidorova, J.M., Yin,J. Wang, W., Monnat, R.J., Jr., Falaschi, A. and Vindigni, A. (2010) The human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation. Molec Cell Biol. 30:1382-1396.
Mao, F.J., Sidorova, J.M., Lauper, J.M., Emond, M.E. and Monnat, R.J., Jr. (2010) The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage. Cancer Research 70(16):6548-55.
Ulge, U.Y., Baker, D.A. and Monnat, R.J., Jr. (2010) Comprehensive computational design of mCreI homing endonuclease cleavage specificity for genome engineering. Nucleic Acids Research 39(10):4330-9.