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

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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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._

AUTHOR INFORMATION Author notes * Fabrizio d'Adda di Fagagna and M. Prakash Hande: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Wellcome/CRC Institute,

Cambridge, Tennis Court Road, CB2 1QR, UK Fabrizio d'Adda di Fagagna & Stephen P. Jackson * Department of Zoology, University of Cambridge, Cambridge, CB2 3EJ, UK Fabrizio

d'Adda di Fagagna & Stephen P. Jackson * Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, V5Z1L3, British Columbia, Canada M. Prakash Hande & Peter M. Lansdorp *

International Agency for Research on Cancer, Lyon, France Wei-Min Tong & Zhao-Qi Wang * Department of Medicine, University of British Columbia, Vancouver, V6T2B5, British Columbia,

Canada Peter M. Lansdorp Authors * Fabrizio d'Adda di Fagagna View author publications You can also search for this author inPubMed Google Scholar * M. Prakash Hande View author

publications You can also search for this author inPubMed Google Scholar * Wei-Min Tong View author publications You can also search for this author inPubMed Google Scholar * Peter M.

Lansdorp View author publications You can also search for this author inPubMed Google Scholar * Zhao-Qi Wang View author publications You can also search for this author inPubMed Google

Scholar * Stephen P. Jackson View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Stephen P. Jackson. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 25 March 1999 * Accepted: 09 August 1999 * Issue Date: September 1999 *

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