Poly(ADP-ribose)polymerase -1 and -2 (PARP-1 and PARP-2) are chromatin-associated proteins involved in multiple facets of DNA-dependent mechanisms, including DNA repair, DNA replication and transcription. These enzymes catalyze the transfer and polymerization of ADP ribose units from NAD+ to form branched polymers of ADP-ribose, called poly(ADP-ribose) (PAR), covalently attached to heterologous acceptor proteins or PARP-1/2 themselves. By interacting with their partners or by poly(ADP-ribosyl)ating target proteins, PARP-1 and PARP-2 regulate chromatin structure and function, and maintain genome integrity.
PARP-dependent mechanism regulating chromatin structure and function
Absence of PARP-1 or PARP-2 leads to the loss heterochromatin integrity, including centromeres and pericentromeres. These two domains are playing an essential role in the correct segregation of chromosomes, which defect may lead to aneuploidy and tumorigenesis. How PARP-1 and PARP-2 preserve centromere and pericentromere organization remains elusive.
Our research interest is to characterize PARP-dependent mechanisms involved in the maintenance of these chromatin domains.
Poly(ADP-ribosyl)ation in Glioblastoma
Glioblastoma (GBM) is the most common primary malignant brain tumor. Despite treatment combining surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ), patient survival remains poor and recurrence is virtually inevitable. There is a growing interest in PARP inhibitors (PARPi) for their clinical potential in cancer treatment. In BRCA-related cancers, they improve radiotherapy and/or chemotherapy. PARPi are currently in clinical trials for patients with GBM. However, the molecular role of PARP activity in GBM remains unknown.
Our goal is to understand the biology of PARP inhibition in GBM and the underlying mechanism of GBM response.
Our research is currently supported by startup funding from the College of Medicine, University of Vermont and the American Cancer Society (Institutional Research Grant 126773-IRG-14-196-01-IRG).