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Nucleic Acids Research, 2003, Vol. 31, No. 21 6198-6205
© 2003 Oxford University Press

Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo

Satoshi Ishizuka1,2,3, Kareen Martin2, Catherine Booth2, Christopher S. Potten2, Gilbert de Murcia4, Alexander Bürkle1 and Thomas B. L. Kirkwood*,1

1 School of Clinical Medical Sciences—Gerontology, Institute for Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne NE4 6BE, UK, 2 CRC Epithelial Biology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK, 3 Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan and 4 Unité 9003 CNRS, Laboratoire conventionné avec le Commissariat à l’Energie Atomique École Supérieure de Biotechnologie de Strasbourg, F-67400 Illkirch-Graffenstaden, France

*To whom correspondence should be addressed. Tel: +44 191 256 3319; Fax: +44 191 219 5074; Email: tom.kirkwood{at}ncl.ac.uk
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme mediating the cellular response to DNA strand breaks. It plays a critical role in genomic stability and survival of proliferating cells in culture undergoing DNA damage. Intestinal epithelium is the most proliferative tissue in the mammalian body and its stem cells show extreme sensitivity to low-level genotoxic stress. We investigated the role of PARP-1 in the in vivo damage response of intestinal stem cells in crypts of PARP-1–/– and control mice following whole-body {gamma}-irradiation (1 Gy). In the PARP-1–/– mice there was a significant delay during the first 6 h in the transient p53 accumulation in stem cells whereas an increased number of cells were positive for p21CIP1/WAF1. Either no or only marginal differences were noted in MDM2 expression, apoptosis, induction of or recovery from mitotic blockage, or inhibition of DNA synthesis. We further observed a dose-dependent reduction in crypt survival measured at 4 days post-irradiation in control mice, and this crypt-killing effect was significantly potentiated in PARP-1–/– mice. Our results thus establish that PARP-1 acts as a survival factor for intestinal stem cells in vivo and suggest a functional link with early p53 and p21CIP1/WAF1 responses.


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