Research interests:

Our focus is to understand how the commitment to the mitotic cell cycle is regulated in response to environmental and internal cues, as well as adversities such as DNA damage. The critical transitions in the eukaryotic cell cycle are controlled by cyclin-dependent kinases (CDKs). Both the structure and function of these CDKs are so highly conserved that the first human CDKs were identified by complementation of mutations in their fission yeast counterparts. The molecular and genetic analysis of yeast continues to provide crucial insights into how these complexes are regulated and what they do. In budding yeast, as in all higher eukaryotes, the decision to commit to another division cycle occurs in G1. Nine cyclins have been identified that bind and activate a single CDK, and three of these cyclins (Cln1,2 and 3) play critical roles in modulating the decision to exit from G1 and begin another cell cycle. We are studying what controls the expression of these three G1 cyclins and other critical cell cycle regulators that are specifically expressed during G1.

There are two consecutive waves of transcription that occur during G1. The first occurs at the M/G1 boundary and we have defined a new promoter element, the ECB, which activates transcription of CLN3 and other key cell cycle regulators at this time. The second wave of transcription is conferred by at least two other promoter elements (SCBs and MCBs), which are activated near the G1/S boundary to induce the expression of CLN1, CLN2 and dozens of other genes that are required for DNA replication and cell wall synthesis. Our goal is to understand how internal and external signals modulate the activity of these transcription complexes and control the timing of the transition to S phase.

Another adaptive feature of the cell cycle in all cells is a set of surveillance mechanisms which delay the cycle when damage occurs. In the case of DNA damage, cells are able to delay in G1, S and/or G2 in order for repair to take place. DNA damage induces a kinase cascade which phosphorylates substrates responsible for the arrest of the cell cycle and the repair. Mutations in the genes in this checkpoint pathway prevent the delay and lead to an increased sensitivity to DNA damage in yeast and humans. We are also investigating the mechanism by which these kinases arrest the cell cycle in G1. Our recent work suggests that the damage-dependent delay of cells in G1 may involve down-regulation of G1 cyclin expression by both transcriptional and post-transcriptional mechanisms.

Publications: (Click on authors to see abstract)

Last update: 8/18/01