title: An ancient protein-DNA interaction underlying metazoan sex determination.
abstract: DMRT transcription factors are deeply conserved regulators of metazoan sexual development. They share the DM DNA-binding domain, a unique intertwined double zinc-binding module followed by a C-terminal recognition helix, which binds a pseudopalindromic target DNA. Here we show that DMRT proteins use a unique binding interaction, inserting two adjacent antiparallel recognition helices into a widened DNA major groove to make base-specific contacts. Versatility in how specific base contacts are made allows human DMRT1 to use multiple DNA binding modes (tetramer, trimer and dimer). Chromatin immunoprecipitation with exonuclease treatment (ChIP-exo) indicates that multiple DNA binding modes also are used in vivo. We show that mutations affecting residues crucial for DNA recognition are associated with an intersex phenotype in flies and with male-to-female sex reversal in humans. Our results illuminate an ancient molecular interaction underlying much of metazoan sexual development.
authors.affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Murphy
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Unit of Human Developmental Genetics, Institut Pasteur, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rojo
authors.affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Micah D
authors.initials: MD
authors.lastname: Gearhart
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kayo
authors.initials: K
authors.lastname: Kurahashi
authors.affiliation: Northeastern Collaborative Access Team, Cornell University, Argonne, Illinois, USA.
authors.forename: Surajit
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Service de Pédiatrie, Centre Hospitalier de Dunkerque, Dunkerque, France.
authors.forename: Guy-André
authors.initials: GA
authors.lastname: Loeuille
authors.affiliation: Unit of Human Developmental Genetics, Institut Pasteur, Paris, France.
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
authors.affiliation: Unit of Human Developmental Genetics, Institut Pasteur, Paris, France.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McElreavey
authors.affiliation: 1] Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA. [2] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [3] Developmental Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zarkower
authors.affiliation: 1] Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA. [2] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Aihara
authors.affiliation: 1] Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA. [2] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [3] Developmental Biology Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Vivian J
authors.initials: VJ
authors.lastname: Bardwell
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004175:Diptera; D005090:Exodeoxyribonucleases; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D012723:Sex; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C110547:DMRT1 protein; D014157:Transcription Factors; D004247:DNA; D005090:Exodeoxyribonucleases