A TOPBP1 allele causing male infertility uncouples XY silencing dynamics from sex body formation.

Autor:	Ascenção C; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States., Sims JR; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States., Dziubek A; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States., Comstock W; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States., Fogarty EA; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States., Badar J; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States., Freire R; Fundación Canaria del Instituto de Investigación Sanitaria de Canarias (FIISC), Unidad de Investigación, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain.; Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain.; Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain., Grimson A; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States., Weiss RS; Department of Biomedical Sciences, Cornell University, Ithaca, United States., Cohen PE; Department of Biomedical Sciences, Cornell University, Ithaca, United States., Smolka MB; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Feb 23; Vol. 12. Date of Electronic Publication: 2024 Feb 23.
DOI:	10.7554/eLife.90887
Abstrakt:	Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key drivers of MSCI within the specialized sex body (SB) domain of the nucleus, how they promote silencing remains unclear given their multifaceted meiotic functions that also include DNA repair, chromosome synapsis, and SB formation. Here we report a novel mutant mouse harboring mutations in the TOPBP1-BRCT5 domain. Topbp1 B5/B5 males are infertile, with impaired MSCI despite displaying grossly normal events of early prophase I, including synapsis and SB formation. Specific ATR-dependent events are disrupted, including phosphorylation and localization of the RNA:DNA helicase Senataxin. Topbp1 B5/B5 spermatocytes initiate, but cannot maintain ongoing, MSCI. These findings reveal a non-canonical role for the ATR-TOPBP1 signaling axis in MSCI dynamics at advanced stages in pachynema and establish the first mouse mutant that separates ATR signaling and MSCI from SB formation. Competing Interests: CA, JS, AD, WC, EF, JB, RF, AG, RW, PC, MS No competing interests declared (© 2023, Ascenção, Sims et al.)
Databáze:	MEDLINE
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