Mammalian BTBD12 (SLX4) Protects against Genomic Instability during Mammalian Spermatogenesis

• DOI: 10.1371/journal.pgen.1002094
• Publication Date: 2011-06-03T11:43:06Z
• Authors: J. Kim Holloway; Swapna Mohan; Gabriel Balmus; Xianfei Sun; Andrew Modzelewski; Peter L. Borst; Raimundo Freire; Robert S. Weiss; Paula E. Cohen
• Keywords: BRCA2 Protein

The mammalian ortholog of yeast Slx4, BTBD12, is an ATM substrate that functions as a scaffold for various DNA repair activities. Mutations human BTBD12 have been reported in new sub-type Fanconi anemia patients. Recent studies implicated the fly and worm orthologs, MUS312 HIM-18, regulation meiotic crossovers arising from double-strand break (DSB) initiating events also genome stability prior to meiosis. Using Btbd12 mutant mouse, we analyzed role gametogenesis. localizes pre-meiotic spermatogonia spermatocytes wildtype males. mice less than 15% normal spermatozoa are subfertile. Loss during embryogenesis results impaired primordial germ cell proliferation increased apoptosis, which reduces spermatogonial pool early postnatal testis. During prophase I, DSBs initiate normally animals. However, DSB delayed or impeded, resulting persistent γH2AX RAD51, choice pathway may be altered, elevated MLH1/MLH3 focus numbers at pachynema. result increase apoptosis through I beyond. Unlike therefore, appears function possibly recombination lead production crossovers. In line with its expected by kinase, protein reduced testis Atm−/− males, exhibit genomic instability form blood micronucleus formation similar seen Taken together, these data indicate throughout gametogenesis maintain stability, co-ordinating processes and/or linking cycle via ATM.