PARP-2 deficiency affects the survival of CD4+CD8+ double-positive thymocytes.
Poly-(ADP-ribose) polymerase-2 (PARP-2) belongs to a large family of enzymes that synthesize and transfer ADP-ribose polymers to acceptor proteins, modifying their functional properties. PARP-2-deficient (Parp-2-/-) cells, similar to Parp-1-/- cells, are sensitive to both ionizing radiation and alkylating agents. Here we show that inactivation of mouse Parp-2, but not Parp-1, produced a two-fold reduction in CD4+CD8+ double-positive (DP) thymocytes associated with decreased DP cell survival. Microarray analyses revealed increased expression of the proapoptotic Bcl-2 family member Noxa in Parp-2-/- DP thymocytes compared to littermate controls. In addition, DP thymocytes from Parp-2-/- have a reduced expression of T-cell receptor (TCR)alpha and a skewed repertoire of TCRalpha toward the 5' Jalpha segments. Our results show that in the absence of PARP-2, the survival of DP thymocytes undergoing TCRalpha recombination is compromised despite normal amounts of Bcl-xL. These data suggest a novel role for PARP-2 as an important mediator of T-cell survival during thymopoiesis by preventing the activation of DNA damage-dependent apoptotic response during the multiple rounds of TCRalpha rearrangements preceding a positively selected TCR.
Yélamos
José
J
Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia, Murcia, Spain. jyelamos@um.es
Monreal
Yolanda
Y
Saenz
Luis
L
Aguado
Enrique
E
Schreiber
Valérie
V
Mota
Rubén
R
Fuente
Teodomiro
T
Minguela
Alfredo
A
Parrilla
Pascual
P
de Murcia
Gilbert
G
Almarza
Elena
E
Aparicio
Pedro
P
Ménissier-de Murcia
Josiane
J
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival; D004249:DNA Damage; D020869:Gene Expression Profiling; D015329:Gene Rearrangement, T-Lymphocyte; D016158:Genes, p53; D038041:Lymphopoiesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction
C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse