Partial rescue of the prophase I defects of Atm-deficient mice by p53 and p21 null alleles.
Patients with the human disorder ataxia-telangiectasia (A-T; refs 1,2) and Atm-deficient mice have a pleiotropic phenotype that includes infertility. Here we demonstrate that male gametogenesis is severely disrupted in Atm-deficient mice in the earliest stages of meiotic prophase I, resulting in apoptotic degeneration. Atm is required for proper assembly of Rad51 onto the chromosomal axial elements during meiosis. In addition, p53, p21 and Bax are elevated in testes from Atm-deficient mice. To determine whether these elevated protein levels are important factors in the meiotic disruption of Atm-deficient mice, we analysed the meiotic phenotype of Atm/p53 or Atm/p21 double mutants. In these double mutants, meiosis progressed to later stages but was only partly rescued. Assembly of Rad51 foci on axial elements remained defective, and gametogenesis proceeded only to pachytene of prophase I. Previous results demonstrated that mice homozygous for a null mutation in Rad51 (ref. 6) display an early embryonic lethal phenotype that can be partly rescued by removing p53 and/or p21. Because Atm-deficient mice are viable but completely infertile, our studies suggest that the Rad51 assembly defects and elevated levels of p53, p21 and Bax represent tissue-specific responses to the absence of Atm.
Barlow
C
C
Laboratory of Genetic Disease Research, National Institute of Diabetes, Digestive and Kidney Disorders, Bethesda, Maryland 20892, USA.
Liyanage
M
M
Moens
P B
PB
Deng
C X
CX
Ried
T
T
Wynshaw-Boris
A
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011418:Prophase / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D051135:Rad51 Recombinase; D013090:Spermatocytes / Q000378:metabolism / Q000648:ultrastructure; D013573:Synaptonemal Complex / Q000235:genetics; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse