Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability

In most eukaryotes, poly(ADP-ribose) polymerase (PARP) recognizes DNA stran d interruptions generated in vivo. DNA binding by PARP triggers primarily i ts own modification by the sequential addition of ADP-ribose units to form polymers; this modification, in turn, causes the release of PARP from DNA e nds(1). Studies on the effects of the disruption of the gene encoding PARP (Adprt1, formerly Adprp) in mice have demonstrated roles for PARP in recove ry from DNA damage and in suppressing recombination processes involving DNA ends(1-5). Telomeres are the natural termini of chromosomes and are, there fore, potential targets of PARP. Here, by the use of two different techniqu es, we show that mice lacking PARP display telomere shortening compared wit h wild-type mice. Telomere shortening is seen in different genetic backgrou nds and in different tissues, both from embryos and adult mice. In vitro te lomerase 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, charac terized by increased frequencies of chromosome fusions and aneuploidy. The absence of PARP does not affect the presence of single-strand overhangs, na turally present at the ends of telomeres. This study therefore reveals an u nanticipated role for PARP in telomere length regulation and provides insig hts into its functions in maintaining genomic integrity.