ADP-ribosylation is a modification of proteins, DNA and RNA in response to intracellular and extracellular signals. This dynamic modification is dependent on a writer PARP1 (Poly(ADP-ribose)polymerase), an eraser, such as PARG (Poly(ADP-ribose)glycohydrolase), and numerous readers. Together, they contribute to the maintenance of cell integrity, by modulating DNA-dependent mechanisms, chromatin structure, cellular signaling, metabolism, mitochondria homeostasis, and cell death.

The development of PARP1 and PARG inhibitors (PARPi and PARGi) has revealed distinct roles of these proteins and their activity. Several PARPi have been FDA-approved for the treatment of specific ovarian. Yet, their broader use in disease treatment has been challenging due to a lack of mechanistic understanding of ADP-ribosylation.Our long-term goal is to further understand the roles of ADP-ribosylation in cell homeostasis.

ADP-ribosylation in metabolism

The post-translational modification ADP-ribosylation has been identified in more than 9,000 proteins, including in the cytoplasm and organelles. Numerous enzymes involved in the carbohydrate metabolism, such as malate dehydrogenase, are ADP-ribosylated; however, the consequence of the presence or absence of this modification is unknown. This project is in association with the Malate Dehydrogenase CURE Community.

ADP-ribosylation-dependent mechanism regulating chromatin structure and function.

Absence of PARP1 leads to the loss of 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 does PARP-1 preserve centromere and pericentromere organization remains elusive.

ADP-ribosylation, as a stress signal

Imbalanced PARylation is sensed as a stress signal, that can stimulate an adaptive response involving the endoplasmic reticulum stress/unfolded protein response (ER stress/UPR) to restore normal function of the cell or induce cell death. This signaling response involves an organized and sophisticated crosstalk between organelles (i.e., ER, nucleus and mitochondria) and molecular pathways. Yet, the functional link between PARylation and ER stress/UPR remains elusive.

ADP-ribosylation in cerebral and glioblastoma organoids

Cellular response to intracellular and extracellular signal is not processed by individual cells, but by whole tissues. Consequently, there is a need to further define how ADP-ribosylation maintains cellular homeostasis in a more complex system. We have established the cerebral and glioblastoma organoid models, a 3D system that recapitulates tissue development, organization and function, to assess how ADP-ribosylation imbalance and cancer treatments are sensed in a tissue-like structure.