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2 results on '"Elinati E"'

1. ATR is a multifunctional regulator of male mouse meiosis.

Author

Widger A, Mahadevaiah SK, Lange J, ElInati E, Zohren J, Hirota T, Pacheco S, Maldonado-Linares A, Stanzione M, Ojarikre O, Maciulyte V, de Rooij DG, Tóth A, Roig I, Keeney S, and Turner JMA

Subjects
Animals, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia Mutated Proteins metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Chromosome Pairing genetics, Chromosomes, Mammalian metabolism, In Situ Hybridization, Fluorescence, Male, Meiotic Prophase I genetics, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nuclear Proteins genetics, Nuclear Proteins metabolism, Phosphate-Binding Proteins, Rad51 Recombinase genetics, Rad51 Recombinase metabolism, Chromosomes, Mammalian genetics, DNA Breaks, Double-Stranded, Meiosis genetics, Spermatocytes metabolism
Abstract

Meiotic cells undergo genetic exchange between homologs through programmed DNA double-strand break (DSB) formation, recombination and synapsis. In mice, the DNA damage-regulated phosphatidylinositol-3-kinase-like kinase (PIKK) ATM regulates all of these processes. However, the meiotic functions of the PIKK ATR have remained elusive, because germline-specific depletion of this kinase is challenging. Here we uncover roles for ATR in male mouse prophase I progression. ATR deletion causes chromosome axis fragmentation and germ cell elimination at mid pachynema. This elimination cannot be rescued by deletion of ATM and the third DNA damage-regulated PIKK, PRKDC, consistent with the existence of a PIKK-independent surveillance mechanism in the mammalian germline. ATR is required for synapsis, in a manner genetically dissociable from DSB formation. ATR also regulates loading of recombinases RAD51 and DMC1 to DSBs and recombination focus dynamics on synapsed and asynapsed chromosomes. Our studies reveal ATR as a critical regulator of mouse meiosis.

Published
2018
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2. DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line.

Author

ElInati E, Russell HR, Ojarikre OA, Sangrithi M, Hirota T, de Rooij DG, McKinnon PJ, and Turner JMA

Subjects
Animals, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia Mutated Proteins metabolism, BRCA1 Protein, Carrier Proteins metabolism, Chromosome Pairing, Histones genetics, Histones metabolism, Male, Mice, Mice, Knockout, Sex Chromosomes metabolism, Spermatids cytology, Spermatids growth & development, Spermatids metabolism, Spermatocytes cytology, Spermatocytes growth & development, Spermatocytes metabolism, Spermatogonia cytology, Spermatogonia growth & development, Spermatogonia metabolism, Spermatozoa cytology, Spermatozoa growth & development, Spermatozoa metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Carrier Proteins genetics, DNA Breaks, Double-Stranded, Sex Chromosomes chemistry, Spermatogenesis genetics, X Chromosome Inactivation
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 (γH2AFX). 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, γH2AFX, 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., Competing Interests: The authors declare no conflict of interest.

Published
2017
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