Published online 3 August 2004
Nucleic Acids Research, Vol. 32 No. 13 © Oxford University Press 2004; all rights reserved
Poly(ADP-ribose) polymerase 1 regulates both the exonuclease and helicase activities of the Werner syndrome protein
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA and 1 UPR 9003 du Centre National de la Recherche Scientifique, Universite Louis Pasteur, Ecole Superieure de Biotechnologie de Strasbourg, 67412 Illkirch Cedex, France
* To whom correspondence should be addressed: Tel: +1 410 558 8162; Fax: +1 410 558 8157; Email: vbohr{at}nih.gov
Present address: Cayetano von Kobbe, Centro Nacional de Investigaciones Oncologicas (CNIO), Telomeres and Telomerase Group, Madrid 28029, Spain
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
Received June 23, 2004; Accepted July 6, 2004
Werner syndrome (WS) is a genetic premature aging disorder in which patients appear much older than their chronological age. The gene mutated in WS encodes a nuclear protein (WRN) which possesses 3'–5' exonuclease and ATPase-dependent 3'–5' helicase activities. The genomic instability associated with WS cells and the biochemical characteristics of WRN suggest that WRN plays a role in DNA metabolic pathways such as transcription, replication, recombination and repair. Recently we have identified poly(ADP-ribose) polymerase-1 (PARP-1) as a new WRN interacting protein. In this paper, we further mapped the interacting domains. We found that PARP-1 bound to the N-terminus of WRN and to the C-terminus containing the RecQ-conserved (RQC) domain. WRN bound to the N-terminus of PARP-1 containing DNA binding and BRCA1 C-terminal (BRCT) domains. We show that unmodified PARP-1 inhibited both WRN exonuclease and helicase activities, and to our knowledge is the only known WRN protein partner that inactivates both of the WRN's catalytic activities suggesting a biologically significant regulation. Moreover, this dual inhibition seems to be specific for PARP-1, as PARP-2 did not affect WRN helicase activity and only slightly inhibited WRN exonuclease activity. The differential effect of PARP-1 and PARP-2 on WRN catalytic activity was not due to differences in affinity for WRN or the DNA substrate. Finally, we demonstrate that the inhibition of WRN by PARP-1 was influenced by the poly(ADP-ribosyl)ation state of PARP-1. The biological relevance of the specific modulation of WRN catalytic activities by PARP-1 are discussed in the context of pathways in which these proteins may function together, namely in the repair of DNA strand breaks.
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