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Title: An ancient protein-DNA interaction underlying metazoan sex determination

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. In this paper, 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. Finally, our results illuminate an ancient molecular interaction underlying much of metazoan sexual development.
Authors:
 [1] ;  [2] ;  [3] ;  [1] ;  [2] ;  [4] ;  [5] ;  [3] ;  [3] ;  [6] ;  [7] ;  [6]
  1. Univ. of Minnesota, Minneapolis, MN (United States). Dept. of Genetics, Cell Biology, and Development
  2. Univ. of Minnesota, Minneapolis, MN (United States). Dept. of Biochemistry, Molecular Biology and Biophysics
  3. Pasteur Inst., Paris (France). Unit of Human Developmental Genetics
  4. Cornell Univ., Argonne, IL (United States). Northeastern Collaborative Access Team
  5. Hospital Center of Dunkirk (France). Pediatric Ward
  6. Univ. of Minnesota, Minneapolis, MN (United States). Dept. of Genetics, Cell Biology, and Development. Masonic Cancer Center. Developmental Biology Center
  7. Univ. of Minnesota, Minneapolis, MN (United States). Dept. of Biochemistry, Molecular Biology and Biophysics. Masonic Cancer Center
Publication Date:
OSTI Identifier:
1184236
Grant/Contract Number:
AC02-06CH11357; P41 GM103403; GM59152; GM50399; AI087098; GM095558; BM1303
Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 6; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Research Org:
Univ. of Minnesota, Minneapolis, MN (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); European Cooperation in Science and Technology (COST) (Belgium)
Contributing Orgs:
Pasteur Inst., Paris (France); Cornell Univ., Argonne, IL (United States); Hospital Center of Dunkirk (France)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; DMRT protein; DM domain; sex determination; DMRT1; DNA-binding proteins; transcription factors