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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. 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:
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 Org.:
Pasteur Inst., Paris (France); Cornell Univ., Argonne, IL (United States); Hospital Center of Dunkirk (France)
OSTI Identifier:
1184236
Grant/Contract Number:  
AC02-06CH11357; P41 GM103403; GM59152; GM50399; AI087098; GM095558; BM1303
Resource Type:
Journal Article: 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
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

Citation Formats

Murphy, Mark W., Lee, John K., Rojo, Sandra, Gearhart, Micah D., Kurahashi, Kayo, Banerjee, Surajit, Loeuille, Guy-André, Bashamboo, Anu, McElreavey, Kenneth, Zarkower, David, Aihara, Hideki, and Bardwell, Vivian J. An ancient protein-DNA interaction underlying metazoan sex determination. United States: N. p., 2015. Web. doi:10.1038/nsmb.3032.
Murphy, Mark W., Lee, John K., Rojo, Sandra, Gearhart, Micah D., Kurahashi, Kayo, Banerjee, Surajit, Loeuille, Guy-André, Bashamboo, Anu, McElreavey, Kenneth, Zarkower, David, Aihara, Hideki, & Bardwell, Vivian J. An ancient protein-DNA interaction underlying metazoan sex determination. United States. https://doi.org/10.1038/nsmb.3032
Murphy, Mark W., Lee, John K., Rojo, Sandra, Gearhart, Micah D., Kurahashi, Kayo, Banerjee, Surajit, Loeuille, Guy-André, Bashamboo, Anu, McElreavey, Kenneth, Zarkower, David, Aihara, Hideki, and Bardwell, Vivian J. 2015. "An ancient protein-DNA interaction underlying metazoan sex determination". United States. https://doi.org/10.1038/nsmb.3032. https://www.osti.gov/servlets/purl/1184236.
@article{osti_1184236,
title = {An ancient protein-DNA interaction underlying metazoan sex determination},
author = {Murphy, Mark W. and Lee, John K. and Rojo, Sandra and Gearhart, Micah D. and Kurahashi, Kayo and Banerjee, Surajit and Loeuille, Guy-André and Bashamboo, Anu and McElreavey, Kenneth and Zarkower, David and Aihara, Hideki and Bardwell, Vivian J.},
abstractNote = {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.},
doi = {10.1038/nsmb.3032},
url = {https://www.osti.gov/biblio/1184236}, journal = {Nature Structural & Molecular Biology},
issn = {1545-9993},
number = 6,
volume = 22,
place = {United States},
year = {Mon May 25 00:00:00 EDT 2015},
month = {Mon May 25 00:00:00 EDT 2015}
}

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Works referencing / citing this record:

The TALE homeodomain of PBX1 is involved in human primary testis‐determination
journal, May 2019


Identification and Characterization of the DMRT11E Gene in the Oriental River Prawn Macrobrachium nipponense
journal, April 2019


Drosophila enhancer-Gal4 lines show ectopic expression during development
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Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD
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Drosophila enhancer-Gal4 lines show ectopic expression during development
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Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD
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DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment
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The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach
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Correction: Corrigendum: Testis-specific transcriptional regulators selectively occupy BORIS-bound CTCF target regions in mouse male germ cells
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