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

Nature Genetics volume 23, pages 76–80 (1999)Cite this article

Abstract

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 ends1. 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 ends1,2,3,4,5. 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.

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Figure 1: FISH analysis of metaphase chromosomal spreads.
Figure 2: Frequency distribution of telomere fluorescence shows telomere shortening associated with the lack of PARP.
Figure 3: Lack of PARP does not affect the presence of single strand overhangs at the telomeres and in vitro telomerase activity.

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Acknowledgements

We thank members of the Jackson lab, in particular D. D'Amours, for helpful discussions; A. Venkitaraman for advice; M. Hemann in C. Greider's lab for advice on the single-strand detection technique; and T. de Lange for the pTH5 plasmid. F.d.'A.d.F. is supported by The Cancer Research Campaign Project grant SP2143/0301. Work by M.P.H. and P.M.L. was supported by a grant from the National Cancer Institute of Canada with funds from the Terry Fox Run. W.-M.T. and Z.-Q.W. are supported by a grant from the Association for International Cancer Research.

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Author notes

  1. Fabrizio d'Adda di Fagagna and M. Prakash Hande: These authors contributed equally to this work.

Authors and Affiliations

  1. Wellcome/CRC Institute, Cambridge, Tennis Court Road, CB2 1QR, UK

    Fabrizio d'Adda di Fagagna & Stephen P. Jackson

  2. Department of Zoology, University of Cambridge, Cambridge, CB2 3EJ, UK

    Fabrizio d'Adda di Fagagna & Stephen P. Jackson

  3. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, V5Z1L3, British Columbia, Canada

    M. Prakash Hande & Peter M. Lansdorp

  4. International Agency for Research on Cancer, Lyon, France

    Wei-Min Tong & Zhao-Qi Wang

  5. Department of Medicine, University of British Columbia, Vancouver, V6T2B5, British Columbia, Canada

    Peter M. Lansdorp

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  1. Fabrizio d'Adda di Fagagna
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Correspondence to Stephen P. Jackson.

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Fagagna, F., Hande, M., Tong, WM. et al. Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability. Nat Genet 23, 76–80 (1999). https://doi.org/10.1038/12680

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