1. DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line
- Author
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ElInati, Elias, Russell, Helen R., Ojarikre, Obah A., Sangrithi, Mahesh, Hirota, Takayuki, De Rooij, Dirk G., McKinnon, Peter J., Turner, James M.A., Developmental Biology, Sub Developmental Biology, Developmental Biology, Sub Developmental Biology, Obstetrics and Gynaecology, Center for Reproductive Medicine, and ARD - Amsterdam Reproduction and Development
- Subjects
Male ,0301 basic medicine ,Ataxia Telangiectasia Mutated Proteins ,Histones ,Mice ,03 medical and health sciences ,Spermatocytes ,X Chromosome Inactivation ,Homologous chromosome ,medicine ,Animals ,Gene silencing ,DNA Breaks, Double-Stranded ,Spermatogenesis ,General ,X chromosome ,Mice, Knockout ,Genetics ,Sex Chromosomes ,Multidisciplinary ,biology ,BRCA1 Protein ,Tumor Suppressor Proteins ,Synapsis ,Biological Sciences ,Spermatids ,Spermatozoa ,Meiotic silencing ,Spermatogonia ,Chromosome Pairing ,Meiosis ,030104 developmental biology ,Histone ,medicine.anatomical_structure ,H2AFX ,Premature chromosome condensation ,biology.protein ,DNA damage ,TOPBP1 ,Carrier Proteins ,Germ cell - Abstract
Meiotic synapsis and recombination between homologs permits the formation of cross-overs that are essential for generating chromosomally balanced sperm and eggs. In mammals, surveillance mechanisms eliminate meiotic cells with defective synapsis, thereby minimizing transmission of aneuploidy. One such surveillance mechanism is meiotic silencing, the inactivation of genes located on asynapsed chromosomes, via ATR-dependent serine-139 phosphorylation of histone H2AFX (gamma H2AFX). Stimulation of ATR activity requires direct interaction with an ATR activation domain (AAD)-containing partner. However, which partner facilitates the meiotic silencing properties of ATR is unknown. Focusing on the best-characterized example of meiotic silencing, meiotic sex chromosome inactivation, we reveal this AAD-containing partner to be the DNA damage and checkpoint protein TOPBP1. Conditional TOPBP1 deletion during pachynema causes germ cell elimination associated with defective X chromosome gene silencing and sex chromosome condensation. TOPBP1 is essential for localization to the X chromosome of silencing "sensors," including BRCA1, and effectors, including ATR, gamma H2AFX, and canonical repressive histone marks. We present evidence that persistent DNA double-strand breaks act as silencing initiation sites. Our study identifies TOPBP1 as a critical factor in meiotic sex chromosome silencing
- Published
- 2017