Full Member (Genetics)
Department of Cancer Biology
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
Telephone: (716) 845-3047
Fax: (716) 845-8126
E-mail: huberman@buffalo.edu

Laboratory Web Pages
Additional information is available from the Huberman laboratory web pages.

General Research Interest

Regulation of DNA Replication

Current Program

Replication timing
Response of DNA replication to DNA damage

Laboratory Personnel

Amna Chaudari
Robert M. Givens PhD
Gerald Jahreis
Sanjay Kumar PhD
Anita Paul MD
Sunita Ramanathan PhD

Description of Research

We are trying to understand how DNA replication is regulated and how abnormalities in its regulation contribute to cancer. We are currently using only yeast cells as model organisms, because yeast cells are easier to study than human cells, and they are very similar to human cells in terms of the mechanisms by which they regulate DNA replication.

DNA replication begins at multiple sites, called "origins", that are distributed at irregular intervals throughout the lengths of chromosomal DNA molecules. Normally replication initiates at certain origins earlier than at other origins. Many studies have shown that activation of origins at the correct time is important for maintenance of genomic stability and for prevention of cancer. Despite the importance of correct replication timing, the mechanisms that permit early origins to fire before late origins have not yet been elucidated. We have identified short stretches of DNA in yeast cells that impose late replication timing on nearby origins, and we are currently trying to identify the proteins that bind to these DNA stretches. The resulting information will provide important clues about the mechanisms that control replication timing.

In both human and yeast cells, initiation of DNA replication at origins is inhibited when DNA is damaged, and this inhibition is mediated in part by standard DNA damage checkpoint proteins. The mechanisms by which checkpoint proteins inhibit replication initiation are still partly unclear. We are taking advantage of powerful yeast genetic techniques to gain improved understanding of these mechanisms.

Further Information

Additional information is available from the Huberman laboratory web pages.

Key Publications

• Marchetti MA, Weinberger M, Murakami Y, Burhans WC, Huberman JA. Production of reactive oxygen species in response to replication stress and inappropriate mitosis in fission yeast. J Cell Sci 119:124-131, 2006.
• Sommariva S, Pellny T.K, Karahan N, Kumar S, Huberman JA, Dalgaard JZ. Schizosaccharomyces pombe Swi1p, Swi3p and Hsk1p are components of a novel S-phase response pathway to alkylation damage. Mol Cell Biol 25:2770-2784, 2005.
• Weinberger M, Ramachandran L, Feng L, Sharma K, Sun X, Marchetti M, Huberman JA, Burhans WC. Apoptosis in budding yeast caused by defects in initiation of DNA replication.  J Cell Sci 118:3543-3553, 2005.
• Kumar S and Huberman JA. On the slowing of S phase in response to DNA damage in fission yeast. J Biol Chem 279:43574-43580, 2004.
• Yompakdee C and Huberman J. Enforcement of late replication origin firing by clusters of short G-rich DNA sequences. J Biol Chem 279:42337-42344, 2004.
• Masukata H, Huberman J, Frattini M, Kelly T. DNA replication in S. pombe. In "The Molecular Biology of Schizosaccharomyces pombe". Genetics, Genomics and Beyond, ed. R. Egel, Spinger-Verlag Heidelberg, pp. 73-99, 2003
• Huberman JA. DNA replication, the cell cycle and genome stability. Mutat Res 532:1-4, 2003.
• Burhans WC, Weinberger M, Marchetti MA, Ramachandran L, D'Urso G, Huberman JA. Apoptosis-like yeast cell death in response to DNA damage and replication defects. Mutat Res 532:227-243, 2003.
• Bowmaker M, Yang M, Yasukawa T, Reyes A, Jacobs H, Huberman J, Holt I. Mammalian mitochondrial DNA replicates bidirectionally from an initiation zone. J Biol Chem 278:50961-50969, 2003.
• Antunes D, Kim S, Huberman JA, DeMorais M. Motifs in Schizosaccharomyces pombe ars3002 important for replication origin activity in Saccharomyces cerevisiae. Plasmid 50:113119, 2003.
• Kim S-M, Dubey DD, Huberman JA. Early-replicating heterochromatin. Genes Dev 17:330-335, 2003.
• Marchetti M, Kumar S, Hartsuiker E, Maftahi M, Carr AM, Freyer GH, Burhans WC, Huberman JA. A single unbranched S-phase DNA damage and replication fork blockage checkpoint pathway. Proc Natl Acad Sci USA 99:7472-7477, 2002.
• Sharma K, Weinberger M, Huberman JA. Roles for internal and flanking sequences in regulating the activity of mating-type-silencer-associated replication origins in Saccharomyces cerevisiae. Genetics 159:35-45, 2001.
• Kim S-M, Zhang D-Y, Huberman JA. Multiple redundant sequence elements within the fission yeast ura4 replication origin enhancer. BMC Molecular Biology 2:1, 2001. <http://www.biomedcentral.com/1471-2199/2/1>.
• Tan D-F, Huberman JA, Hyland A, Loewen G, Brooks JSJ, Beck A, Slocum HK, Ramnath N, Todorov IT, Bepler G. MCM2-- A promising marker for premalignant lesions of the lung. BMC Cancer 1:6, 2001. <http://www.biomedcentral.com/1471-2407/1/6>.
• Kim S-M, and Huberman JA. Regulation of replication timing in fission yeast. EMBO J 20: 6115-6126, 2001.
• Berezney R, Dubey DD, Huberman JA. Heterogeneity of eukaryotic replicons, replicon clusters, and replication foci. Chromosoma 108: 471-484, 2000.
• Kim S-M, and Huberman JA. Influence of a replication enhancer on the hierarchy of origin efficiencies within a cluster of DNA replication origins. J Mol Biol 288:867-882, 1999.
• Weinberger M, Trabold PA, Lu M, Sharma K, Huberman JA, Burhans WC. Induction by antitumor agents of ORC-dependent DNA damage and DNA replication checkpoints in S. cerevisiae. J Biol Chem 274:35975-35984, 1999.
• Huberman JA. Genetic methods for characterizing the cis-acting components of yeast DNA replication origins. Methods: A Companion to Methods in Enzymology 18:356-367, 1999.
• Huberman JA. DNA damage and replication checkpoints in the fission yeast, Schizosaccharomyces pombe. Progr Nucl Acids Res Mol Biol 62:369-395, 1999.