Our focus is on eukaryotic DNA replication and its control, with emphasis on the identification of the protein components involved in these processes. In general, eukaryotic replication proceeds along pathways that have been conserved from yeast to mammalian cells, and strikingly, as we gain more detailed information, appears to extend to prokaryotes.
All initiation events commence with the formation of a multimeric complex at the origin of initiation. In SV40 DNA replication, the origin binding protein is SV40 T antigen, an 82 kDa protein that multimerizes at the origin in the presence of ATP. In eukaryotes, the origin binding protein is a six subunit complex, the origin recognition complex (ORC). In S. cerevisiae, ORC is bound to origins of replication throughout the cell cycle . In G1, ORC recruits additional replication proteins, including Cdt1, Cdc6p and the MCM family of proteins, to form a pre-replicative complex (Pre-RC). This is followed by the addition of Mcm10p, Cdc45 and a number of other proteins, including the replicative polymerases to the complex. At the initiation of S-phase, Cdc6p is degraded and the MCM proteins and Cdc45p are found to move with the replication fork. Similar observations have been made in Xenopus extracts with proteins and complexes homologous to those found in S. cerevisiae.
Our laboratory has divided eukaryotic replication into multiple stages, and we are studying enzymes that participate in both the initiation and elongation stages.
Bermudez VP, Farina A, Tappin I, Hurwitz J. Influence of the cohesion establishment factor human Ctf4/AND-1 on DNA replication. J Biol Chem. 2010 Mar 26;285(13):9493-505. doi: 10.1074/jbc.M109.093609. Epub 2010 Jan 19.
Bermudez VP, Farina A, Raghavan V, Tappin I, Hurwitz J. Studies on human DNA polymerase epsilon and GINS and their role in DNA replication. J Biol Chem. 2011 Aug 19;286(33):28963-77. doi: 10.1074/jbc.M111.256289. Epub 2011 Jun 24.
Bermudez VP, Farina A, Higashi TL, Du F, Tappin I, Takahashi TS, Hurwitz J. In vitro loading of DNA by the human Scc2-Sc4 complex. Proc Natl Acad Sci USA. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9366-71. doi: 10.1073/pnas. 1206840109. Epub 2012 May 24.
Cho WH, Kang YH, An YY, Tappin I, Hurwitz J, Lee JK. Human Tim-Tipin complex affects the biochemical properties of the replicative DNA helicase and DNA polymerases. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2523-7. doi: 10.1073/pnas.1222494110. Epub 2013 Jan 28.
Yardimci H, Wang X, Loveland AB, Tappin I, Rudner DZ, Hurwitz J, van Oijen AM, Walter JC. Bypass of a protein barrier by a replicative DNA helicase. Nature. 2012 Dec 13;492(7428):205-9. doi: 10.1038/nature11730. Epub 2012 Nov 28.
Pfizer Science Award, History of Science Society (1984-1989)
Louis and Bert Freeman Foundation Prize for Research, New York Academy of Science (1982)
Fogarty Scholar Award, Fogarty International Center (1980)
Member, National Academy of Sciences (1974)
Fellow, John SimonGuggenheim Memorial Foundation (1968)
Professorship, American Cancer Society (1963-1998)
Eli Lilly Award in Biochemistry, American Chemistry Society (1962)
Sigma Xi Award (1962)
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