Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability.
In most eukaryotes, poly(ADP-ribose) polymerase (PARP) recognizes DNA strand interruptions generated in vivo. DNA binding by PARP triggers primarily its own modification by the sequential addition of ADP-ribose units to form polymers; this modification, in turn, causes the release of PARP from DNA ends. Studies on the effects of the disruption of the gene encoding PARP (Adprt1, formerly Adprp) in mice have demonstrated roles for PARP in recovery from DNA damage and in suppressing recombination processes involving DNA ends. Telomeres are the natural termini of chromosomes and are, therefore, potential targets of PARP. Here, by the use of two different techniques, we show that mice lacking PARP display telomere shortening compared with wild-type mice. Telomere shortening is seen in different genetic backgrounds and in different tissues, both from embryos and adult mice. In vitro telomerase activity, however, is not altered in Adprt1-/- mouse fibroblasts. Furthermore, cytogenetic analysis of mouse embryonic fibroblasts reveals that lack of PARP is associated with severe chromosomal instability, characterized by increased frequencies of chromosome fusions and aneuploidy. The absence of PARP does not affect the presence of single-strand overhangs, naturally present at the ends of telomeres. This study therefore reveals an unanticipated role for PARP in telomere length regulation and provides insights into its functions in maintaining genomic integrity.
d'Adda di Fagagna
F
F
Wellcome/CRC Institute, Tennis Court Road, Cambridge, CB2 1QR, UK.
Hande
M P
MP
Tong
W M
WM
Lansdorp
P M
PM
Wang
Z Q
ZQ
Jackson
S P
SP
D000782:Aneuploidy; D000818:Animals; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000502:physiology*; D003433:Crosses, Genetic; D004262:DNA Restriction Enzymes / Q000378:metabolism; D005347:Fibroblasts; D005838:Genotype; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009693:Nucleic Acid Hybridization; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000502:physiology*; D016615:Telomere / Q000235:genetics / Q000502:physiology*
D011065:Poly(ADP-ribose) Polymerases; D004262:DNA Restriction Enzymes