Multiple 9-1-1 complexes promote homolog synapsis, DSB repair, and ATR signaling during mammalian meiosis

eLife

Vitor M Faca¹  Gerardo A Arroyo-Martinez²  Carl J Schiltz²  Paula E Cohen²  Catalina Pereira²  Matthew Z Guo²  Michael S Downey²  Robert S Weiss²  Charlton Tsai²  Nathan L Clark³  Jennie R Sims⁴  Marcus B Smolka⁴  Kathryn J Grive⁵  Niek Wit⁶  Heinz Jacobs⁶  Amy M Lyndaker⁷  Emma R Kelly⁷  Miguel A Brieno-Enriquez⁸  James Turner⁹  Shantha K Mahadevaiah⁹  Raimundo Freire^1,10 

[1] Department of Biochemistry and Immunology, FMRP, University of São Paulo, Ribeirão Preto, Brazil;Department of Biomedical Sciences, Cornell University, Ithaca, United States;Department of Human Genetics, University of Utah, Salt Lake City, United States;Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, United States;Department of Obstetrics and Gynecology, Brown University, Providence, United States;Division of Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands;Division of Mathematics and Natural Sciences, Elmira College, Elmira, United States;Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, United States;Sex Chromosome Biology Laboratory, The Francis Crick Institute, London, United Kingdom;Unidad de Investigación, Hospital Universitario de Canarias, Tenerife, Spain;Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain;Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain;

关键词: meiosis;    DNA damage response;    DNA break repair;    meiotic silencing;    9-1-1 complex;    ATR;    Mouse;   

DOI  :  10.7554/eLife.68677

来源: eLife Sciences Publications, Ltd

【 摘 要 】

DNA damage response mechanisms have meiotic roles that ensure successful gamete formation. While completion of meiotic double-strand break (DSB) repair requires the canonical RAD9A-RAD1-HUS1 (9A-1-1) complex, mammalian meiocytes also express RAD9A and HUS1 paralogs, RAD9B and HUS1B, predicted to form alternative 9-1-1 complexes. The RAD1 subunit is shared by all predicted 9-1-1 complexes and localizes to meiotic chromosomes even in the absence of HUS1 and RAD9A. Here, we report that testis-specific disruption of RAD1 in mice resulted in impaired DSB repair, germ cell depletion, and infertility. Unlike Hus1 or Rad9a disruption, Rad1 loss in meiocytes also caused severe defects in homolog synapsis, impaired phosphorylation of ATR targets such as H2AX, CHK1, and HORMAD2, and compromised meiotic sex chromosome inactivation. Together, these results establish critical roles for both canonical and alternative 9-1-1 complexes in meiotic ATR activation and successful prophase I completion.

【 授权许可】

CC BY