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

Journal Article · · Nature Structural & Molecular Biology
DOI:https://doi.org/10.1038/nsmb.3032· OSTI ID:1184236
 [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

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.

Research Organization:
Univ. of Minnesota, Minneapolis, MN (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); European Cooperation in Science and Technology (COST) (Belgium)
Contributing Organization:
Pasteur Inst., Paris (France); Cornell Univ., Argonne, IL (United States); Hospital Center of Dunkirk (France)
Grant/Contract Number:
AC02-06CH11357; P41 GM103403; GM59152; GM50399; AI087098; GM095558; BM1303
OSTI ID:
1184236
Journal Information:
Nature Structural & Molecular Biology, Vol. 22, Issue 6; ISSN 1545-9993
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 74 works
Citation information provided by
Web of Science

References (55)

Sex determination journal April 2012
Model-based Analysis of ChIP-Seq (MACS) journal January 2008
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Orchestrating high-throughput genomic analysis with Bioconductor journal January 2015
Female-to-male sex reversal in mice caused by transgenic overexpression of Dmrt1 journal February 2015
DNAshape: a method for the high-throughput prediction of DNA structural features on a genomic scale journal May 2013
Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm journal June 2009
GBshape: a genome browser database for DNA shape annotations journal October 2014
A human XY female with a frame shift mutation in the candidate testis-determining gene SRY journal November 1990
3DNA: a versatile, integrated software system for the analysis, rebuilding and visualization of three-dimensional nucleic-acid structures journal July 2008
Trimmomatic: a flexible trimmer for Illumina sequence data journal April 2014
Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development journal May 2012
Evidence for evolutionary conservation of sex-determining genes journal February 1998
OTG-snpcaller: An Optimized Pipeline Based on TMAP and GATK for SNP Calling from Ion Torrent Data journal May 2014
A W-linked DM-domain gene, DM-W, participates in primary ovary development in Xenopus laevis journal February 2008
Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation journal October 2000
Genome-wide analysis of DNA binding and transcriptional regulation by the mammalian Doublesex homolog DMRT1 in the juvenile testis journal July 2010
Fast and accurate long-read alignment with Burrows–Wheeler transform journal January 2010
A sex-specific transcription factor controls male identity in a simultaneous hermaphrodite journal May 2013
XDS journal January 2010
Sex and the singular DM domain: insights into sexual regulation, evolution and plasticity journal February 2012
Crystallographic Analysis of a Sex-Specific Enhancer Element: Sequence-Dependent DNA Structure, Hydration, and Dynamics journal January 2009
Five-Vertebrate ChIP-seq Reveals the Evolutionary Dynamics of Transcription Factor Binding journal April 2010
The role of DNA shape in protein–DNA recognition journal October 2009
Deletions of Distal 9p Associated with 46,XY Male to Female Sex Reversal: Definition of the Breakpoints at 9p23.3–p24.1 journal April 1997
Vertebrate DM domain proteins bind similar DNA sequences and can heterodimerize on DNA journal January 2007
DMY is a Y-specific DM-domain gene required for male development in the medaka fish journal May 2002
Site-directed mutagenesis by overlap extension using the polymerase chain reaction journal April 1989
DMRT1 prevents female reprogramming in the postnatal mammalian testis journal July 2011
A method and server for predicting damaging missense mutations journal April 2010
ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors journal February 2015
Principles of regulatory information conservation between mouse and human journal November 2014
MEME SUITE: tools for motif discovery and searching journal May 2009
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
Identification of De Novo Copy Number Variants Associated with Human Disorders of Sexual Development journal October 2010
Features and development of Coot journal March 2010
Quantitative DNase footprint titration: a tool for analyzing the energetics of protein–DNA interactions journal May 2008
Comprehensive Genome-wide Protein-DNA Interactions Detected at Single-Nucleotide Resolution journal December 2011
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Origins of Specificity in Protein-DNA Recognition journal June 2010
Association of deletion 9p, 46,XY gonadal dysgenesis and autistic spectrum disorder journal June 2007
Over-expression of DMRT1 induces the male pathway in embryonic chicken gonads journal May 2014
Absence of a simple code: how transcription factors read the genome journal September 2014
Pre-mRNA splicing in the absence of an SR protein RS domain journal December 2000
The Drosophila doublesex proteins share a novel zinc finger related DNA binding domain. journal February 1993
Dmrt genes in the development and evolution of sexual dimorphism journal April 2012
The Sequence Alignment/Map format and SAMtools journal June 2009
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Software for Computing and Annotating Genomic Ranges journal August 2013
mab-3, a gene required for sex-specific yolk protein expression and a male-specific lineage in C. elegans journal September 1988
The avian Z-linked gene DMRT1 is required for male sex determination in the chicken journal August 2009
Sequence-specific recognition of double helical nucleic acids by proteins. journal March 1976
Sexual Cell-Fate Reprogramming in the Ovary by DMRT1 journal March 2015
SEX AND THE SINGLE CELL. I. ON THE ACTION OF MAJOR LOCI AFFECTING SEX DETERMINATION IN DROSOPHILA MELANOGASTER journal February 1980
Similarity of DNA binding and transcriptional regulation by Caenorhabditis elegans MAB-3 and Drosophila melanogaster DSX suggests conservation of sex determining mechanisms journal March 1999

Cited By (22)

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 journal March 2017
Developmental expression of “germline”- and “sex determination”-related genes in the ctenophore Mnemiopsis leidyi journal August 2016
Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD journal October 2019
Potential involvement of a DMRT family member ( Mr‐Dsx ) in the regulation of sexual differentiation and moulting in the giant river prawn Macrobrachium rosenbergii journal July 2019
Insights from resolving protein–DNA interactions at near base-pair resolution journal December 2017
Sex-specific pruning of neuronal synapses in Caenorhabditis elegans journal May 2016
The Gonadal Supporting Cell Lineage and Mammalian Sex Determination: The Differentiation of Sertoli and Granulosa Cells book June 2016
DNAshapeR: an R/Bioconductor package for DNA shape prediction and feature encoding journal December 2015
Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development: Anomalies in human sex determination journal January 2017
DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment journal September 2016
Immunolocalization of DMRTB1 in human testis with normal and impaired spermatogenesis journal March 2019
The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach journal November 2019
Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children journal March 2018
DNAproDB: an interactive tool for structural analysis of DNA–protein complexes journal April 2017
Correction: Corrigendum: Testis-specific transcriptional regulators selectively occupy BORIS-bound CTCF target regions in mouse male germ cells journal August 2017
A genetic switch for worker nutrition-mediated traits in honeybees journal March 2019
DMRT1 repression using a novel approach to genetic manipulation induces testicular dysgenesis in human fetal gonads journal September 2018
Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development journal January 2016
Parallel Evolution of Two dmrt1-Derived Genes, dmy and dm-W, for Vertebrate Sex Determination journal January 2020
Sex determination and maintenance: the role of DMRT1 and FOXL2 journal January 2017