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Nucleic Acids Research Advance Access published online on July 4, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn403
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility

Camille Godon1,2, Fabrice P. Cordelières1,3,4, Denis Biard5, Nicole Giocanti1,2, Frédérique Mégnin-Chanet1,2, Janet Hall1,2 and Vincent Favaudon1,2,*

1Institut Curie, Centre de Recherche 2Inserm, U612, 3CNRS, UMR146, 4Plateforme d’Imagerie Cellulaire et Tissulaire, Institut Curie, Bât. 110-112, Centre Universitaire, F-91405 Orsay and 5Commissariat à l'Energie Atomique, CEA-DSV-IRCM, Inserm U602, Hôpital Paul Brousse, Bât. Lavoisier, 12-16 avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France

*To whom correspondence should be addressed. Tel: +33 169 86 3188; Fax: +33 169 86 3187; Email: vincent.favaudon{at}curie.fr

Received March 14, 2008. Revised June 5, 2008. Accepted June 9, 2008.

The consequences of PARP-1 disruption or inhibition on DNA single-strand break repair (SSBR) and radio-induced lethality were determined in synchronized, isogenic HeLa cells stably silenced or not for poly(ADP-ribose) polymerase-1 (PARP-1) (PARP-1KD) or XRCC1 (XRCC1KD). PARP-1 inhibition prevented XRCC1-YFP recruitment at sites of 405 nm laser micro irradiation, slowed SSBR 10-fold and triggered the accumulation of large persistent foci of GFP-PARP-1 and GFP-PCNA at photo damaged sites. These aggregates are presumed to hinder the recruitment of other effectors of the base excision repair (BER) pathway. PARP-1 silencing also prevented XRCC1-YFP recruitment but did not lengthen the lifetime of GFP-PCNA foci. Moreover, PARP-1KD and XRCC1KD cells in S phase completed SSBR as rapidly as controls, while SSBR was delayed in G1. Taken together, the data demonstrate that a PARP-1- and XRCC1-independent SSBR pathway operates when the short patch repair branch of the BER is deficient. Long patch repair is the likely mechanism, as GFP-PCNA recruitment at photo-damaged sites was normal in PARP-1KD cells. PARP-1 silencing elicited hyper-radiosensitivity, while radiosensitization by a PARP inhibitor reportedly occurs only in those cells treated in S phase. PARP-1 inhibition and deletion thus have different outcomes in terms of SSBR and radiosensitivity.


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