Area of interest
Genome instability is a major cause of cancer. Many pathways have evolved to maintain genome stability; mutations that inactivate these pathways in humans are frequently associated with diseases that involve a predisposition to malignancy. Our research concerns mechanisms of maintaining genome stability and the consequences of genome instability. To learn more about these topics we use the model organism Drosophila melanogaster (the fruit fly), though we have also expanded our investigations into mammalian cell culture. Our primary approach is genetic (classical and molecular, forward and reverse), but we also employ genomic, biochemical, and structural approaches.
Our major focus has been on pathways for repairing DNA double-strand breaks (DSBs). DSBs arise spontaneously during DNA replication or from exposure to ionizing radiation or certain chemical mutagens. Our work addresses repair of DSBs in proliferating cells and in meiotic recombination. In proliferating cells, we have focused on the function of the RecQ helicase DmBLM. Defects in human BLM cause Bloom syndrome, which is associated with an extremely high predisposition to cancer. We have found a specific role for DmBLM in repairing DSBs via the predominant pathway for repair. This is a pathway that does not generate crossovers. In the absence of DmBLM, repair is error-prone, frequently resulting in deletions, and is often associated with crossovers.
While our mitotic work focuses on mechanisms that prevent crossing over, our meiotic work focuses specifically on proteins required to make crossovers, which are required to ensure correct chromosome segregation. In Drosophila, MEI-9 and MUS312 are known to be involved in generating crossovers from a meiotic recombination intermediate. MEI-9 is the Drosophila homolog of XPF, the structure-specific endonuclease that plays an important role in nucleotide excision repair. Mutations in human XPF result in xeroderma pigmentosum, which is associated with extreme sensitivity to sunlight and childhood onset of skin cancer. XPF interacts with ERCC1 in all known functions (the same is true of the yeast homologs). We have found that the MEI-9/ERCC1 heterodimer also interacts with the novel DNA repair protein MUS312 to make meiotic crossovers. We are currently testing whether the MEI-9/ERCC1/MUS312 complex has novel activities, including Holliday junctions cleavage activity. We've also identified human MUS312, shown that it interacts with human XPF, and discovered a specific defect in repairing interstrand crosslinks (ICLs) in DNA, a particularly nasty type of lesion. ICLs are clinically important because many chemotherapy agents, including the first ever used, work by inducing ICLs.
Awards and Honors
Ellison Medical Foundation New Scholar Award, 2000-2004
American Cancer Society Research Scholar, 2005-2009
Glenn Foundation Award for Research into Biological Mechanisms of Aging, 2008-2010
Elected Fellow of the American Association for the Advancement of Science (AAAS), 2012