DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse.
Ercc1 is essential for nucleotide excision repair (NER) but, unlike other NER proteins, Ercc1 and Xpf are also involved in recombination repair pathways. Ercc1 knockout mice have profound cell cycle abnormalities in the liver and die before weaning. Subsequently Xpa and Xpc knockouts have proved to be good models for the human NER deficiency disease, xeroderma pigmentosum, leading to speculation that the recombination, rather than the NER deficit is the key to the Ercc1 knockout phenotype. To investigate the importance of the recombination repair functions of Ercc1 we studied spermatogenesis and oogenesis in Ercc1-deficient mice. Male and female Ercc1-deficient mice were both infertile. Ercc1 was expressed at a high level in the testis and the highest levels of Ercc1 protein occurred in germ cells following meiotic crossing over. However, in Ercc1 null males some germ cell loss occurred prior to meiotic entry and there was no evidence that Ercc1 was essential for meiotic crossing over. An increased level of DNA strand breaks and oxidative DNA damage was found in Ercc1-deficient testis and increased apoptosis was noted in male germ cells. We conclude that the repair functions of Ercc1 are required in both male and female germ cells at all stages of their maturation. The role of endogenous oxidative DNA damage and the reason for the sensitivity of the germ cells to Ercc1 deficiency are discussed.
Hsia
Kan-Tai
KT
Institute of Cell and Molecular Biology, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.
Millar
Michael R
MR
King
Sasha
S
Selfridge
Jim
J
Redhead
Nicola J
NJ
Melton
David W
DW
Saunders
Philippa T K
PT
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D005854:Germ Cells / Q000502:physiology*; D006801:Humans; D007246:Infertility / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009866:Oogenesis / Q000502:physiology*; D010053:Ovary / Q000166:cytology; D010084:Oxidation-Reduction; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013091:Spermatogenesis / Q000502:physiology*; D013094:Spermatozoa / Q000166:cytology / Q000502:physiology; D013737:Testis / Q000166:cytology; D014018:Tissue Distribution; D019076:Transgenes; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D011506:Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; C499360:Ercc1 protein, mouse