Loss of poly(ADP-ribose) polymerase-2 leads to rapid development of spontaneous T-cell lymphomas in p53-deficient mice

Abstract

Poly(ADP-ribose) polymerase-2 (Parp-2) belongs to a family of enzymes that catalyse poly(ADP-ribosyl)ation of proteins. Parp-2 deficiency in mice (Parp-2) results in reduced thymic cellularity associated with increased apoptosis in thymocytes, defining Parp-2 as an important mediator of T-cell survival during thymopoiesis. To determine whether there is a link between Parp-2 and the p53 DNA-damage-dependent apoptotic response, we have generated Parp-2/p53-double-null mutant mice. We found that p53 À/À backgrounds completely restored the survival and development of Parp-2 À/À thymocytes. However, Parp-2-deficient thymocytes accumulated high levels of DNA double-strand breaks (DSB), independently of the p53 status, in line with a function of Parp-2 as a caretaker promoting genomic stability during thymocytes development. Although Parp-2 À/À mice do not have spontaneous tumours, Parp-2 deficiency accelerated spontaneous tumour development in p53-null mice, mainly T-cell lymphomas. These data suggest a synergistic interaction between Parp-2 and p53 in tumour suppression through the role of Parp-2 in DNA-damage response and genome integrity surveillance, and point to the potential importance of examining human tumours for the status of both genes.

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

“…Nicolás and co-workers have identified the accumulation of double strand breaks in PARP-2 -/-murine thymocytes [38]. This observation is in line with previous report by Yelamos and colleagues [24] who suggested that PARP-2 interacts with the Ku proteins, mediators of double strand break repair.…”

“…Increased expression of a pro-apoptotic, bcl-2 homolog NOXA showed correlation with the enhanced apoptosis [47]. Apoptosis can be reversed by the removal of p53 [38] suggesting that cell death is induced by unresolved DNA damage. In line with this observation, when PARP-2 -/-mice were bred on a p53 -/-background, spontaneous lymphomas and to a smaller extent other sarcomas developed in the double knockout mice 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 [38] indicating a functional interplay between these two proteins in protecting genome integrity.…”

“…Furthermore, PARP-2 is also engaged in tumorigenesis. In mice the double deletion of PARP-2 and p53 induced spontaneous lymphomas and certain sarcomas [38] and decreased expression of PARP-2 correlated with increased susceptibility to alkylatorinduced acute myeloid leukemia (AML) [48]. Results from these experimental models suggest that PARP-2 has a dominant role in suppressing leukemias [49].…”

Co-targeting Deoxyribonucleic Acid–Dependent Protein Kinase and Poly(Adenosine Diphosphate-Ribose) Polymerase-1 Promotes Accelerated Senescence of Irradiated Cancer Cells

“…Although PARP-1 and PARP-2 have a wellestablished role in base excision repair of single-strand DNA breaks (6), these enzymes also participate in DSB repair (7)(8)(9). Poly(ADP-ribose) polymerase 1 contributes to DSB repair by regulating the stress-inducible transcription factor nuclear factor kB and is a key molecular driver in the DSB repair pathway backup NHEJ (B-NHEJ) (10)(11)(12)(13).…”

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

“…PARP-2 was abundantly expressed in the subcapsular zone of the thymus with decreased expression towards the center of the thymus suggestive of its involvement in thymocyte proliferation [11]. Indeed, PARP-2 deficient thymocytes die via p53-mediated apoptosis that leads to decreased number of CD4 + , CD8 + thymocytes in the thymus [12,13].…”