Wold, Marc - University of Iowa - Department of Biochemistry

个人简介

Education BS, Chemistry, California Institute of Technology PhD, Biochemistry, The Johns Hopkins University Post Doctoral Fellow, Molecular Biology & Genetics, The Johns Hopkins University

研究领域

The human genome is composed of ~3 billion base pairs of DNA. In order to grow, a human cell must precisely duplicate this entire genome each cell cycle and continuously protect it from damage or modification. Defects in DNA replication or repair result in higher rates of mutation, chromosome instability and have a direct role in a number of human diseases such as contributing to the development of cancer or causing genetic diseases such as Fragile X and Xeroderma Pigmentosum. Replication protein A (RPA) is a multi-functional, single-stranded DNA-binding protein. RPA is essential for DNA replication, DNA repair, recombination and coordination of the cellular response to DNA damage. RPA is composed of six structurally conserved DNA binding domains that are distributed in three subunits. The functions of these domains are poorly understood. RPA is also phosphorylated during S-phase and in response to DNA damage. Recent studies have shown that RPA hyper-phosphorylation modulates RPA activity and plays a role in the cellular response to DNA damage; however, the mechanism of this regulation is also poorly understood. Our current research focuses on utilizing a combination of in vitro and in vivo approaches to define functions of the domains of RPA and understanding the role of RPA in regulating cellular DNA metabolism. We are using molecular approaches to generate specific mutant forms of RPA. Biochemical and structural analyses are used to define the interactions of RPA with the different DNA substrates and protein complexes. We have also have recently established a system that uses RNAi and plasmid directed expression of exogenous genes to examine the activity of wild-type and mutant RPA genes in human cells. These studies will lead to a better understanding of the molecular mechanisms of cellular DNA metabolism and will contribute to developing new treatments for diseases associated with defects in DNA repair or replication.

近期论文

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Chen, R., Subramanyam, S., Elcock, A. H., Spies, M. & Wold, M. S. (2016). Dynamic binding of replication protein a is required for DNA repair.. Nucleic acids research, 44(12), 5758-72. DOI: 10.1093/nar/gkw339. Myler, L. R., Gallardo, I. F., Zhou, Y., Gong, F., Yang, S. H., Wold, M. S., Miller, K. M., Paull, T. T. & Finkelstein, I. J. (2016). Single-molecule imaging reveals the mechanism of Exo1 regulation by single-stranded DNA binding proteins.. Proceedings of the National Academy of Sciences of the United States of America, 113(9), E1170-9. DOI: 10.1073/pnas.1516674113. Chen, R., Wold, M. (2014). Replication protein A: single-stranded DNA's first responder: dynamic DNA-interactions allow replication protein A to direct single-strand DNA intermediates into different pathways for synthesis or repair. Bioessays, 36(12), 1156-61. DOI: 10.1002/bies.201400107. Sommers, J., Banerjee, T., Hinds, T., Wan, B., Wold, M., Lei, M. & Brosh, R. J. (2014). Novel function of the Fanconi anemia group J or RECQ1 helicase to disrupt protein-DNA complexes in a replication protein A-stimulated manner. J Biol Chem, 289(29), 19928-41. DOI: 10.1074/jbc.M113.542456. Nguyen, B., Sokoloski, J., Galletto, R., Elson, E., Wold, M. & Lohman, T. (2014). Diffusion of human replication protein A along single-stranded DNA. J Mol Biol, 426(19), 3246-61. DOI: 10.1016/j.jmb.2014.07.014. Hass, C. S., Chen, R. & Wold, M. S. (2012). Detection of posttranslational modifications of replication protein A. Methods in molecular biology (Clifton, N.J.), 922, 193-204. Hass, C. S., Lam, K. & Wold, M. S. (2012). Repair-specific functions of replication protein A. The Journal of biological chemistry, 287(6), 3908-18. Sparks, J. L., Kumar, R., Singh, M., Wold, M. S., Pandita, T. K. & Burgers, P. M. (2012). Human exonuclease 5 is a novel sliding exonuclease required for genome stability. The Journal of biological chemistry, 287(51), 42773-83. Lindsey-Boltz, L. A., Reardon, J. T., Wold, M. S. & Sancar, A. (2012). In vitro analysis of the role of replication protein A (RPA) and RPA phosphorylation in ATR-mediated checkpoint signaling. The Journal of biological chemistry, 287(43), 36123-31. Kemp, M. G., Mason, A. C., Carreira, A., Reardon, J. T., Haring, S. J., Borgstahl, G. E., Kowalczykowski, S. C., Sancar, A. & Wold, M. S. (2010). An alternative form of replication protein a expressed in normal human tissues supports DNA repair. The Journal of biological chemistry, 285(7), 4788-97.