Specific Clinical/Research Interest: Regulation of the cell cycle; control over genomic stability and chromosome dynamics; the design of novel strategies for anti-cancer therapies

Current Students: Kevin Barnum and Nagma Shah

Postdoctoral Fellows: Claudia Tapia-Alveal, Su-Jiun Lin

Research Associate: Cara Reynolds, Aaron Yeoh

Summary of Research Studies:
Perhaps the most fundamental process in biology is that by which one cell becomes two. Our research focuses on two related aspects of the biology that controls the integrity of the genome.

1. We study the control of the cell division cycle, and the signaling pathways (checkpoints) that respond to chromosomal damage and prevent cell cycle progression until that damage is repaired.

DNA damage checkpoints function throughout the cell cycle. Those working in G1 phase to prevent the replication of damaged DNA are almost invariably mutated or inactivated in cancers. These defects contribute not only to the instability of tumor cell genomes, but can also knock-out pro-apoptotic pathways, rendering tumors resistant to treatment. Those functioning in G2 phase to prevent commitment to mitosis are, however, virtually always intact and appear to be required for the viability of tumor cells that lack G1 checkpoints. Our research is geared to dissect the molecular and cell biology of G2 checkpoints, and aims to use this knowledge in the design and testing of targeted anti-cancer therapies. Taking genetic and genomic approaches, we utilize fission yeast as a gene and pathway discovery tool, and then apply this information to studies in human cells. We are currently focusing our efforts into: (1) the regulation and function of a checkpoint effector protein kinase, Chk1, informing its suitability as a target in anti-cancer therapy; and (2) the initiating events that modify lesions in DNA into structures that signal the checkpoint and can be repaired.

2. We are investigating how determinants of chromosome structure regulate chromosome segregation and DNA repair, with an emphasis on events that occur during DNA replication.

Chromosomes are highly dynamic structures. They undergo massive reorganization to enable DNA replication and chromosome segregation to occur. This is under the control of the DNA topoisomerases, and three related and interacting Structural Maintenance of Chromosomes(SMC) complexes known as cohesin, condensin and the Smc5/6 complex. Defects in the processes controlled by these enzymes are a potent inducer of chromosome segregation defects leading to changes in chromosome number (aneuploidy). Their function during DNA replication appears to be particularly important, where they control recombination to ensure a complete round of replication by overcoming obstacles that block polymerases, which is then followed by chromosome reorganization in preparation for mitosis. With the importance of replication fidelity, cells have back-up mechanisms controlled by a multi-BRCT domain protein (Brc1/PTIP) and the post-replication repair (PRR) machinery. We are focusing our efforts to understanding how these various genome integrity determinants are integrated in time and space to ensure accurate replication and division of the genome.

The O'Connell Laboratory

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