PARylation 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 (e.g., WWE-, PBZ- or macro-containing protein). Together, they contribute to the maintenance of cell integrity, by modulating DNA-dependent mechanisms (e.g., DNA repair, DNA replication and transcription), chromatin structure, cellular signaling, 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 various cancers, including ovarian cancer mutated in the DNA repair factor BRCA1. PARPi improve the response to radiotherapy and/or chemotherapy and induce cell death. Yet, their broader use in tumor treatment has been challenging due to a lack of mechanistic understanding of PARylation. There is a compelling need to further understand PARP1- and PARG-dependent mechanisms in both physiological and stress environments and to thoroughly characterize the PARylation function in biological control.

Our long-term goal is to further understand the dual role of PARylation in cell fate.

PARylation-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.

Our research interest is to characterize PARP-dependent mechanisms involved in the maintenance of these chromatin domains.

PARylation, 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.

Our research interest is to characterize molecular consequences of PARylation imbalance on ER stress/UPR pathway functionality for the choice between cell survival and death.

PARylation, as a therapeutic target for 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. PARPi are currently in clinical trials for patients with GBM, due to their property to cross the blood brain barrier. However, the molecular role of PARP activity in GBM remains unknown.

Our research interest is to understand the biology of PARP inhibition in GBM and the underlying mechanism of GBM response.

PARylation 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 PARylation maintain 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 PARylation imbalance and cancer treatments are sensed in a tissue-like structure.

Our research interest is to provide fundamental insights on PARylation-dependent mechanisms by taking in account the cellular architecture of normal and cancer tissues.