The overarching goal of my research is to decipher the roles played by Poly(ADP-ribose) polymerases (PARPs) in the maintenance of genome stability.
PARP1 is a key component of the cellular stress response, and functions as both a stress sensor and response mediator. Cellular stress can arise from various intrinsic and extrinsic sources including exposure to numerous environmental agents (i.e. ultraviolet light, oxidants, alkylating chemicals, etc.), and can include the generation of DNA damage, mutations and DNA replicative stress. Stress responses can trigger pathological conditions including inflammatory diseases, metabolic dysregulation, accelerated aging and cancer. Notably, epidemiological studies show that more than 20% of all cancers are caused by chronic inflammation associated with oxidative stress. PARP1 activity is involved in the cellular fate decision of survival or death, depending on the stress severity. In this regard, PARP1 inhibitors are being developed as therapeutics for different cancers, mainly for DNA repair deficient tumors in a context of synthetic lethality.
One aspect of my research more specifically focuses on the roles of PARP1 in the preservation of telomeric DNA integrity. Telomeres are nucleoprotein structures that cap and protect linear chromosomes. They shorten progressively with each chromosomal replication, leading to their uncapping and ultimately to cell death or senescence, or to chromosomal instability in premalignant cells. Importantly, telomeric DNA is highly sensitive to oxidative and replicative stress that can arise from both endogenous and environmental sources leading to accelerated telomere shortening. Thus, oxidative stress increases risks of cancer development and aging related diseases.
More than 85% of cancer cells upregulate the enzyme telomerase in an attempt to maintain their telomere length. Therefore, telomerase is a promising target for cancer therapy. For instance, some telomerase inhibitors are already in phase II trials in combination with DNA damaging agents for treating breast, lung and prostate cancers.
My research aims to provide crucial insights in understanding oxidative stress mediated tumorigenesis by uncovering the roles played by PARP in the maintenance of telomere integrity under stress conditions and in the regulation of telomerase enzyme. Deciphering the mechanisms of PARP1 functions in telomere maintenance will provide new strategies and alternatives for treating cancers and inform the rational design of PARP1-directed therapeutic strategies.
Approaches: We utilize biochemical, molecular and cell biological tools to address our current questions. We developed a highly innovative tool that allows for the local induction of oxidative DNA damage in mammalian cells.