An Ancient Protein-DNA Interaction Underlying Metazoan Sex Determination

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2015 May 26

PMID 26005864

Citations 47

Authors

Mark W Murphy

John K Lee

Sandra Rojo

Micah D Gearhart

Kayo Kurahashi

Surajit Banerjee

Guy-Andre Loeuille

Anu Bashamboo

Kenneth McElreavey

David Zarkower

Hideki Aihara

Vivian J Bardwell

Affiliations

Soon will be listed here.

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.

Citing Articles

Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility.

Maric T, Castillo-Madeen H, Klaric M, Barisic A, Trgovec-Greif L, Murphy M Hum Mol Genet. 2025; 34(6):481-491.

PMID: 39777458 PMC: 11891871. DOI: 10.1093/hmg/ddae197.

Identification and characterization of the Dmrt1B gene in the oriental river prawn, Macrobrachium nipponense.

Jiang G, Xue Y, Arifuzzaman A, Huang X Dev Genes Evol. 2024; 234(1):21-32.

PMID: 38616194 DOI: 10.1007/s00427-024-00715-3.

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study.

Brauner R, Bignon-Topalovic J, Bashamboo A, McElreavey K PLoS One. 2023; 18(12):e0292664.

PMID: 38096238 PMC: 10721018. DOI: 10.1371/journal.pone.0292664.

In Tandem Intragenic Duplication of Doublesex and Mab-3-Related Transcription Factor 1 () in an -Negative Boy with a 46,XX Disorder of Sex Development.

Bertini V, Baldinotti F, Parma P, Tyutyusheva N, Sepich M, Bertolucci G Genes (Basel). 2023; 14(11).

PMID: 38003010 PMC: 10671459. DOI: 10.3390/genes14112067.

is a testis-determining gene in rabbits and is also essential for female fertility.

Dujardin E, Andre M, Dewaele A, Mandon-Pepin B, Poulat F, Frambourg A Elife. 2023; 12.

PMID: 37847154 PMC: 10581690. DOI: 10.7554/eLife.89284.

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