Loss of poly(ADP-ribose) polymerase-2 leads to rapid development of spontaneous T-cell lymphomas in p53-deficient mice.
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(-/-) backgrounds completely restored the survival and development of Parp-2(-/-) 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(-/-) 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.
Nicolás
L
L
Department of Immunology, IMIM-Hospital del Mar, Barcelona Biomedical Research Park, Barcelona, Spain.
Martínez
C
C
Baró
C
C
Rodríguez
M
M
Baroja-Mazo
A
A
Sole
F
F
Flores
J M
JM
Ampurdanés
C
C
Dantzer
F
F
Martin-Caballero
J
J
Aparicio
P
P
Yelamos
J
J
D000818:Animals; D053903:DNA Breaks, Double-Stranded; D005260:Female; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse