title: Clamping down on mammalian meiosis.
abstract: The RAD9A-RAD1-HUS1 (9-1-1) complex is a PCNA-like heterotrimeric clamp that binds damaged DNA to promote cell cycle checkpoint signaling and DNA repair. While various 9-1-1 functions in mammalian somatic cells have been established, mounting evidence from lower eukaryotes predicts critical roles in meiotic germ cells as well. This was investigated in 2 recent studies in which the 9-1-1 complex was disrupted specifically in the mouse male germline through conditional deletion of Rad9a or Hus1. Loss of these clamp subunits led to severely impaired fertility and meiotic defects, including faulty DNA double-strand break repair. While 9-1-1 is critical for ATR kinase activation in somatic cells, these studies did not reveal major defects in ATR checkpoint pathway signaling in meiotic cells. Intriguingly, this new work identified separable roles for 9-1-1 subunits, namely RAD9A- and HUS1-independent roles for RAD1. Based on these studies and the high-level expression of the paralogous proteins RAD9B and HUS1B in testis, we propose a model in which multiple alternative 9-1-1 clamps function during mammalian meiosis to ensure genome maintenance in the germline.
authors.affiliation: Department of Biomedical Sciences; Cornell University; Ithaca, NY USA
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lyndaker
authors.affiliation: Center for Radiological Research; College of Physicians and Surgeons; Columbia University Medical Center; New York, NY USA
authors.forename: Ana
authors.initials: A
authors.lastname: Vasileva
authors.affiliation: Genetics & Development and Obstetrics & Gynecology; The Institute of Human Nutrition; Herbert Irving Comprehensive Cancer Center; Columbia University Medical Center; New York, NY USA
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wolgemuth
authors.affiliation: Department of Biomedical Sciences; Cornell University; Ithaca, NY USA
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.affiliation: Department of Environmental Health Sciences; Mailman School of Public Health; Columbia University Medical Center; New York, NY USA.
authors.forename: Howard B
authors.initials: HB
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D005092:Exonucleases / Q000378:metabolism*; D005298:Fertility; D005854:Germ Cells / Q000378:metabolism; D008297:Male; D008540:Meiosis; D051379:Mice; D011995:Recombination, Genetic; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; C509939:Hus1 protein, mouse; C069930:rad9 protein; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D005092:Exonucleases; C559924:Rad1 protein, mouse
keywords: ATR; HUS1B; RAD9A-RAD1-HUS1 complex; RAD9B; TOPBP1; double-strand break repair; meiosis; pachytene checkpoint; synapsis