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A Single Nucleotide in an Estrogen-Related Receptor Site Can Dictate Mode of Binding and Peroxisome Proliferator-Activated Receptor Coactivator 1 Activation of Target Promoters

Molecular Oncology Group (J.B.B., J.L., V.G.), McGill University Health Centre and Departments of Biochemistry (J.L., V.G.), Medicine and Oncology, McGill University, Montréal, Québec, Canada H3A 1A1

Address all correspondence and requests for reprints to: Dr. Vincent Giguère, Molecular Oncology Group, Room H5-21, McGill University Health Centre, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: vincent.giguere{at}mcgill.ca.

The orphan nuclear receptor estrogen-related receptor (ERR, NR3B1) is a constitutively active transcription factor that controls multiple processes, most notably mitochondrial function. ERR preferentially binds to a nine-nucleotide extended half-site sequence TNAAGGTCA, referred to as the ERRE, as either a monomer or a dimer, although how the mode of DNA binding is dictated remains to be determined. Here, we used variants of the extended half-site sequence and selective DNA binding domain mutants of ERR to investigate the effects of ERRE sequence specificity on ERR DNA binding mode, transactivation and interaction with the coactivator protein peroxisome proliferator-activated receptor coactivator 1 (PGC-1). We found that the base at the N position of the TNAAGGTCA sequence dictated ERR binding preference as a monomer or dimer. In addition, we demonstrated that the threonine residue at position 124 (Thr¹²⁴) was a determinant of ERR DNA-dependent dimerization. Transfection experiments also indicated that substituting a thymidine for a cytosine at the N position in the ERRE of the native ERR target promoter trefoil factor 1 (TFF1) considerably diminished the transcriptional response of the ERR/PGC-1 complex. These results suggest that a single nucleotide in an ERR binding site can determine specific configuration to the receptor and productive interaction with the coactivator PGC-1.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERRα

Coregulators:   PGC-1

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