Functional interaction between poly(ADP-Ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2.
The DNA damage-dependent poly(ADP-ribose) polymerase-2 (PARP-2) is, together with PARP-1, an active player of the base excision repair process, thus defining its key role in genome surveillance and protection. Telomeres are specialized DNA-protein structures that protect chromosome ends from being recognized and processed as DNA strand breaks. In mammals, telomere protection depends on the T(2)AG(3) repeat binding protein TRF2, which has been shown to remodel telomeres into large duplex loops (t-loops). In this work we show that PARP-2 physically binds to TRF2 with high affinity. The association of both proteins requires the N-terminal domain of PARP-2 and the myb domain of TRF2. Both partners colocalize at promyelocytic leukemia bodies in immortalized telomerase-negative cells. In addition, our data show that PARP activity regulates the DNA binding activity of TRF2 via both a covalent heteromodification of the dimerization domain of TRF2 and a noncovalent binding of poly(ADP-ribose) to the myb domain of TRF2. PARP-2(-/-) primary cells show normal telomere length as well as normal telomerase activity compared to wild-type cells but display a spontaneously increased frequency of chromosome and chromatid breaks and of ends lacking detectable T(2)AG(3) repeats. Altogether, these results suggest a functional role of PARP-2 activity in the maintenance of telomere integrity.
Dantzer
Françoise
F
UPR 9003 du Centre National de la Recherche Scientifique, Université Louis Pasteur, Ecole Supérieure de Biotechnologie de Strasbourg, 67412 Illkirch Cedex, France.
Giraud-Panis
Marie-Josèphe
MJ
Jaco
Isabel
I
Amé
Jean-Christophe
JC
Schultz
Inès
I
Blasco
Maria
M
Koering
Catherine-Elaine
CE
Gilson
Eric
E
Ménissier-de Murcia
Josiane
J
de Murcia
Gilbert
G
Schreiber
Valérie
V
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002842:Chromatids / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000378:metabolism; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism; D004249:DNA Damage; D005347:Fibroblasts; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D035341:Telomeric Repeat Binding Protein 2; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; D019098:Telomerase