Dr. Jennifer Cobb

• Genome instability as a consequence of replication of fragile DNA sites

Genomic instability is a hallmark of cancer. Genomic rearrangements are thought to be the means by which cells develop aberrant characteristics that drive their conversion into cancer cells. A central thrust of our laboratory is to characterize early events that lead to chromosomal instability and tumorigenesis.

Our research focuses on genomic instability that arises during DNA replication and double strand break (DSB) repair. Replication forks can collapse and cause DNA damage if mishaps are encountered when duplicating in the genome. We aim to understand how the architecture of the fork is preserved during stress and to characterize the factors that tether broken ends of DNA together at DSBs, preventing them.

One major question in cancer genetics is to what extent chromosomal instability is the beginning of tumorigenesis. RecQ helicases have been called caretakers of the genome and it is well documented that the loss of RecQ function leads to the breakdown in the maintenance of genome integrity and an elevated predisposition to cancer. We are investigating the function of RecQ at the molecular level using Saccharomyces cerevisiae as a model system. It is quite evident that mechanisms that preserve genome stability in yeast are indeed the same as those which go awry in many mammalian cancers. We are focusing on the relationship between Sgs1 and the MRX complex and determining if RecQ helicases preserve fragile site stability in slow replicating regions of the genome.

We are also interested to understand the mechanism of checkpoint activation during S phase. In particular how Mec1-Ddc2 (human ATR-ATRIP) is recruited to stalled replication forks to stabilize components of the replisome. It is well understood that Mec1-Ddc2 activates Rad53 and that it is recruited to both DSBs and stalled replication forks. However, much of what is thought to happen at stalled replication forks has been implied from events at DSBs. In mammals the affinity of ATRIP for RPA suggests a model in which ATR-ATRIP is recruited to DSBs through interaction with RPA-bound single-stranded DNA (ssDNA). Currently, we are characterizing Mec1-Ddc2 localization to stalled replication forks and the signals/factors involved in its recruitment.