Studying the Immunomodulatory Functions of PARP1 and PARP2 in Mouse Models of Cancer.

Poly-ADP-ribosylation of proteins, mediated by the two ADP-ribosyltransferases PARP1 and PARP2 in response to DNA damage, has emerged as a critical mediator of the DNA damage response (DDR). Accordingly, considering the critical role of DDR in cancer, PARP inhibitors (PARPi) have become an important class of therapeutics. PARPi have largely been considered for their intrinsic actions to tumor cells per se.

Impact of DNA Damage Response-Targeted Therapies on the Immune Response to Tumours.

The DNA damage response (DDR) maintains the stability of a genome faced with genotoxic insults (exogenous or endogenous), and aberrations of the DDR are a hallmark of cancer cells. These cancer-specific DDR defects present new therapeutic opportunities, and different compounds that inhibit key components of DDR have been approved for clinical use or are in various stages of clinical trials. Although the therapeutic rationale of these DDR-targeted agents initially focused on their action against tumour cells themselves, these agents might also impact the crosstalk between tumour cells and the immune system, which can facilitate or impede tumour progression.

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice.

Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage.

Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice.

Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis.