Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase-deficient mice and primary cells despite increased chromosomal instability

Poly(ADP-ribose) polymerase (PARP)-1, a detector of single-strand breaks, p lays a key role in the cellular response to DNA damage. PARP-1-deficient mi ce are hypersensitive to genotoxic agents and display genomic instability d ue to a DNA repair defect in the base excision repair pathway. A previous r eport suggested that PARP-1-deficient mice also had a severe telomeric dysf unction consisting of telomere shortening and increased end-to-end fusions (d'Adda di Fagagna, F., M.P. Hande, W.-M. Tong, P.M. Lansdorp, Z.-Q. Wang, and S.P. jackson. 1999. Nat. Genet. 23: 76-80). In contrast to that, and us ing a panoply of techniques, including quantitative telomeric (Q)-FISH, we did not find significant differences in telomere length between wild-type a nd PARP-1(-/-) littermate mice or PARP-1(-/-) primary cells. Similarly, the re were no differences in the length of the G-strand overhang. Q-FISH and s pectral karyotyping analyses of primary PARP-1(-/-) cells showed a frequenc y of 2 end-to-end fusions per 100 metaphases, much lower than that describe d previously (d'Adda di Fagagna et al., 1999). This low frequency of end-to -end fusions in PARP-1-/- primary cells is accordant with the absence of se vere proliferative defects in PARP-1(-/-) mice. The results presented here indicate that PARP-1 does not play a major role in regulating telomere leng th or in telomeric end capping, and the chromosomal instability of PARP-1(- /-) primary cells can be explained by the repair defect associated to PARP- 1 deficiency. Finally, no interaction between PARP-1 and the telomerase rev erse transcriptase subunit, Tert, was found using the two-hybrid assay.