title: Elucidation of the Fanconi Anemia Protein Network in Meiosis and Its Function in the Regulation of Histone Modifications.
abstract: Precise epigenetic regulation of the sex chromosomes is vital for the male germline. Here, we analyze meiosis in eight mouse models deficient for various DNA damage response (DDR) factors, including Fanconi anemia (FA) proteins. We reveal a network of FA and DDR proteins in which FA core factors FANCA, FANCB, and FANCC are essential for FANCD2 foci formation, whereas BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis. In addition, FA proteins modulate distinct histone marks on the sex chromosomes: FA core proteins and FANCD2 regulate H3K9 methylation, while FANCD2 and RNF8 function together to regulate H3K4 methylation independently of FA core proteins. Our data suggest that RNF8 integrates the FA-BRCA pathway. Taken together, our study reveals distinct functions for FA proteins and illuminates the male sex chromosomes as a model to dissect the function of the FA-BRCA pathway.
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: Kris G
authors.initials: KG
authors.lastname: Alavattam
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: Ho-Su
authors.initials: HS
authors.lastname: Sin
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: So
authors.initials: S
authors.lastname: Maezawa
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Kowalski
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.affiliation: Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 49229, USA. Electronic address: satoshi.namekawa@cchmc.org.
authors.forename: Satoshi H
authors.initials: SH
authors.lastname: Namekawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism; D018797:Cell Cycle Proteins; D053903:DNA Breaks, Double-Stranded; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008540:Meiosis; D008745:Methylation; D051379:Mice; D011499:Protein Processing, Post-Translational; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012730:Sex Chromosomes / Q000378:metabolism; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C508937:MDC1 protein, mouse; D051135:Rad51 Recombinase; D008239:Lysine
keywords: DNA damage response; DNA repair; Fanconi anemia; X chromosome; epigenetics; germ cells; meiosis; meiotic sex chromosome inactivation; sex chromosomes; spermatogenesis