deletion of genes implicated in protecting the integrity of male germ cells has differential effects on the incidence of dna breaks and germ cell loss删除基因涉及保护男性生殖细胞的完整性差影响dna断裂的发病率和生殖细胞损失.pdfVIP

Deletion of Genes Implicated in Protecting the Integrity of Male Germ Cells Has Differential Effects on the Incidence of DNA Breaks and Germ Cell Loss 1 2 2 2 2 1 Catriona Paul , Joanne E. Povey , Nicola J. Lawrence , Jim Selfridge , David W. Melton , Philippa T. K. Saunders * 1 Medical Research Council Human Reproductive Sciences Unit, Queen’s Medical Research Institute, Edinburgh, United Kingdom, 2 Sir Alastair Currie Cancer Research United Kingdom Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom Background. Infertility affects ,20% of couples in Europe and in 50% of cases the problem lies with the male partner. The impact of damaged DNA originating in the male germ line on infertility is poorly understood but may increase miscarriage. Mouse models allow us to investigate how deficiencies in DNA repair/damage response pathways impact on formation and function of male germ cells. We have investigated mice with deletions of ERCC1 (excision repair cross-complementing gene 1), MSH2 (MutS homolog 2, involved in mismatch repair pathway), and p53 (tumour suppressor gene implicated in elimination of germ cells with DNA damage). Principal Findings. We demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells. Sertoli cell-only tubules were detected in testes from mice lacking expression of ERCC1 or MSH2 but not p53. The number of sperm recovered from epididymes was significantly reduced in mice lacking testicular ERCC1 and 40% of sperm contained DNA breaks whereas the numbers of sperm were not different to controls in adult Msh2 2/ 2 or p53 2/ 2 mice