Karlene Cimprich

Research/Lab website:   Mole Pharm Lab Site

My lab is focused on understanding the mechanism that the cell uses to maintain genomic stability, with an emphasis on DNA damage checkpoints. Components of these checkpoints effectively monitor the status of the genome, sensing the presence of DNA damage and coordinating a range of possible responses, including DNA repair, apoptosis, transcription, and the arrest of cell cycle progression. Loss of this checkpoint response is a hallmark of cancer cells and is one of the early steps in the development of cancer.

We are studying the DNA damage response using both cell-free extracts derived from the eggs of the frog Xenopus laevis as well as cultured mammalian cells. We are using these systems and a range of multidisciplinary techniques to understand how the checkpoint is activated following DNA damage and how this pathway is integrated with the processes of DNA replication, cell cycle progression and DNA repair.

Specific areas of current interest are:

1) Checkpoint Activation. The actual nature of the signal(s) sensed by the cell and the mechanism by which damage detection occurs is not known. We have found that replication plays a critical role in this process, and we are now working to define the nature of the signal formed during DNA replication and the precise role of replication in generating this signal.

2) Checkpoint Signaling. Using biochemical and microscopy-based approaches, we study the proteins that recognize the checkpoint activating signal, including ATR, ATRIP and the 9-1-1 complex. We are interested in how these proteins are regulated and the role that protein localization plays in this process. We are also working to identify downstream targets of the checkpoint relevant to repair, cell cycle arrest and checkpoint recovery.

3) Chemical Modulation of Checkpoint Pathways. We are using small, organic molecules to analyze checkpoint activation, profile the activity of the checkpoint kinases and identify new targets of the checkpoint. We are also developing new assays to screen for molecules that activate or inhibit the DNA damage checkpoint.