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.

*DNA Repair, *Embryo and Fetal Development, 0 (DNA-Binding Proteins), 0 (Fungal Proteins), 0 (RAD23 protein, fungal), Animals, Body Weight, Cell Line, Cell Survival, Craniofacial Abnormalities/embryology/genetics, DNA-Binding Proteins/chemistry/*genetics/physiology, Dose-Response Relationship, Radiation, Eye/pathology, Female, Fertility, Fibroblasts/physiology/radiation effects, Fungal Proteins/chemistry/*genetics/physiology, Gene Targeting, Human, Infertility, Male/*genetics, Male, Mice, Mice, Transgenic, Organ Weight, Placenta/pathology, Spermatogenesis, Support, Non-U.S. Gov't, Support, U.S. Gov't, P.H.S., Testis/pathology/physiology/physiopathology, Ultraviolet Rays
hdl.handle.net/1765/3193
Molecular and Cellular Biology
Erasmus MC: University Medical Center Rotterdam

Ng, J.M.Y, Vrieling, H, Sugasawa, K, Ooms, M.P, Grootegoed, J.A, Vreeburg, J.T.M, … van der Horst, G.T.J. (2002). Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B. Molecular and Cellular Biology, 22, 1233–1245. Retrieved from http://hdl.handle.net/1765/3193