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Molecular and Cellular Biology, February 2002, p. 1233-1245, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.1233-1245.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Developmental Defects and Male Sterility in Mice Lacking the Ubiquitin-Like DNA Repair Gene mHR23B

MGC-Department of Cell Biology and Genetics, Centre for Biomedical Genetics,¹ Department of Endocrinology and Reproduction, Erasmus University Rotterdam, Rotterdam,⁵ MGC-Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, 2333 AL Leiden,² National Institute of Public Health and the Environment, 3720 BA Bilthoven,⁶ The Netherlands Ophthalmic Research Institute-KNAW, 1105 BA Amsterdam, The Netherlands,⁷ Cellular Physiology Laboratory, RIKEN (The Institute of Physical and Chemical Research),³ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Wako, Saitama 351-0198,⁴ Institute for Molecular and Cellular Biology, Osaka University, Suita, Osaka 565-0871, Japan⁸

Received 23 August 2001/ Returned for modification 27 September 2001/ Accepted 29 October 2001

mHR23B encodes one of the two mammalian homologs of Saccharomyces cerevisiae RAD23, a ubiquitin-like fusion protein involved in nucleotide excision repair (NER). Part of mHR23B is complexed with the XPC protein, and this heterodimer functions as the main damage detector and initiator of global genome NER. While XPC defects exist in humans and mice, mutations for mHR23A and mHR23B are not known. Here, we present a mouse model for mHR23B. Unlike XPC-deficient cells, mHR23B^-/- mouse embryonic fibroblasts are not UV sensitive and retain the repair characteristics of wild-type cells. In agreement with the results of in vitro repair studies, this indicates that mHR23A can functionally replace mHR23B in NER. Unexpectedly, mHR23B^-/- mice show impaired embryonic development and a high rate (90%) of intrauterine or neonatal death. Surviving animals display a variety of abnormalities, including retarded growth, facial dysmorphology, and male sterility. Such abnormalities are not observed in XPC and other NER-deficient mouse mutants and point to a separate function of mHR23B in development. This function may involve regulation of protein stability via the ubiquitin/proteasome pathway and is not or only in part compensated for by mHR23A.

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