title: BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis.
abstract: During meiosis, DNA damage response (DDR) proteins induce transcriptional silencing of unsynapsed chromatin, including the constitutively unsynapsed XY chromosomes in males. DDR proteins are also implicated in double strand break repair during meiotic recombination. Here, we address the function of the breast cancer susceptibility gene Brca1 in meiotic silencing and recombination in mice. Unlike in somatic cells, in which homologous recombination defects of Brca1 mutants are rescued by 53bp1 deletion, the absence of 53BP1 did not rescue the meiotic failure seen in Brca1 mutant males. Further, BRCA1 promotes amplification and spreading of DDR components, including ATR and TOPBP1, along XY chromosome axes and promotes establishment of pericentric heterochromatin on the X chromosome. We propose that BRCA1-dependent establishment of X-pericentric heterochromatin is critical for XY body morphogenesis and subsequent meiotic progression. In contrast, BRCA1 plays a relatively minor role in meiotic recombination, and female Brca1 mutants are fertile. We infer that the major meiotic role of BRCA1 is to promote the dramatic chromatin changes required for formation and function of the XY body.
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Broering
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Kris G
authors.initials: KG
authors.lastname: Alavattam
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Sadreyev
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ichijima
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Camerini-Otero
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114.
authors.forename: Jeannie T
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 satoshi.namekawa@cchmc.org.
authors.forename: Satoshi H
authors.initials: SH
authors.lastname: Namekawa
mesh_terms: D000483:Alleles; D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology*; D023902:Chromosome Pairing; D002875:Chromosomes / Q000378:metabolism; D004249:DNA Damage; D005091:Exons; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D006570:Heterochromatin / Q000235:genetics*; D008297:Male; D008540:Meiosis; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011995:Recombination, Genetic; D013091:Spermatogenesis; D014960:X Chromosome / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D006570:Heterochromatin