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Cyrus Vaziri, Ph.D.
Associate Professor, Cancer Research Center
Associate Professor of Genetics & Genomics
Ph.D. 1992, University of Dundee, U.K.

(617)638-4175

cvaziri@bu.edu

 

 

Our laboratory studies regulation of the cell cycle. In particular, we are interested in tumor suppressive mechanisms termed cell cycle 'checkpoints'. Checkpoints are signal transduction pathways that respond to DNA damage by exerting negative controls over cell cycle progression. The resulting cell cycle delays allow integration of DNA repair with cycle progression. Thus, checkpoints are widely hypothesized to minimize mutagenic events that could result from inaccurate DNA replication. Two of the major ongoing projects in the lab are described below.

DNA damage-induced S-phase checkpoints.

B[a]P-Induced S-phase checkpoints.

We have defined new cell cycle checkpoints elicited by the DNA-damaging environmental carcinogen benzo[a]pyrene (B[a]P). In cells containing the tumor suppressor protein p53, B[a]P-induced DNA damage elicits a cell cycle arrest in early S-phase that results from post-translational downregulation of the S-phase cyclin, Cyclin A. In p53-deficient cells, an alternative checkpoint mechanism involving the checkpoint kinase Chk1 mediates S-phase arrest. Current projects are aimed at identifying both the upstream DNA damage-sensing components and the distal effectors of the checkpoint pathways we have identified.

 

Re-replication checkpoints.

Effect of DNA over-replication in normal cells and cancer cells

Cells possess mechanisms that normally restrict DNA replication to once per cell cycle. Otherwise, over-replication of the genome could contribute to gene amplification and cancer. We have identified a novel checkpoint mechanism that prevents DNA from over-replicating within a single cell cycle. Interestingly, this 're-replication checkpoint' is present in normal cells with intact checkpoint pathways, but is absent from many cancer cell lines that lack the tumor suppressor p53. Current studies are aimed at understanding the mechanisms that sense over-replicated DNA and the effector pathways that are activated as a result of DNA re-replication.

 

Relevant recent publications

Vaziri, C., Saxena, S., Jeon, Y., Lee, C., Hwang, D. S., and Dutta (2002) "Re-replication induced in human cancer cells by over-expression of initiation factors Cdt1 and Cdc6". - Submitted

Weiss, R., Leder, P., and Vaziri, C. (2003) "A Critical Role for Mouse Hus1 in a S-phase DNA Damage Cell Cycle Checkpoint". Mol. Cell Biol. - 23, 791-803. reprint (401 KB, PDF)

Guo, N., Faller, D. V., and Vaziri, C. (2002) "Carcinogen-Induced S-phase is Chk1-Mediated and Caffeine-Sensitive". Cell Gr. Diff. 13, 77-86. reprint (270 KB, PDF)

Nghiem, P., Park, P., Kim, Y., Vaziri, C., and Schreiber, S. (2001) "Selective Induction of Premature Chromatin Condensation in Rapidly Dividing Cells by Interference with ATR Function". Proc. Natl. Acad. Sci. U.S.A. 98, 9092-9097. reprint (331 KB, PDF)

Hsing, A., Faller, D. V., and Vaziri, C. (2000) "DNA-damaging Aryl-hydrocarbons Induce Mdm2 Expression via p53-Independent Post-transcriptional Mechanisms". J. Biol. Chem 275, 26024-26031. reprint (246 KB, PDF)

Guo, N., Faller, D. V., and Vaziri, C. (2000) "A Novel DNA Damage Checkpoint Involving Post-transcriptional Regulation of Cyclin A Expression" J. Biol. Chem. 275, 1715-1722. reprint (276 KB, PDF)

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