Open AccessAn ancient protein-DNA interaction underlying metazoan sex determination
Author(s) -
Mark W. Murphy,
John K. Lee,
Sandra Rojo,
Micah D. Gearhart,
Kayo Kurahashi,
Surajit Banerjee,
Guy André Loeuille,
Anu Bashamboo,
Kenneth McElreavey,
David Zarkower,
Hideki Aihara,
Vivian J. Bardwell
Publication year - 2015
Publication title -
nature structural and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.448
H-Index - 270
eISSN - 1545-9993
pISSN - 1545-9985
DOI - 10.1038/nsmb.3032
Subject(s) - biology , dna , antiparallel (mathematics) , hmg box , chromatin immunoprecipitation , genetics , tetramer , dna binding protein , dna binding domain , dna binding site , base pair , protein–dna interaction , binding site , transcription factor , gene , promoter , gene expression , biochemistry , physics , quantum mechanics , magnetic field , enzyme
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.