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Dimerization of FIR upon FUSE DNA binding suggests a mechanism of c‐myc inhibition
Author(s) -
Crichlow Gregg V,
Zhou Hongwen,
Hsiao Hsinhao,
Frederick Kendra B,
Debrosse Maxime,
Yang Yuande,
FoltaStogniew Ewa J,
Chung HyeJung,
Fan Chengpeng,
De La Cruz Enrique M,
Levens David,
Lolis Elias,
Braddock Demetrios
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601936
Subject(s) - haven , library science , computer science , mathematics , combinatorics
c‐myc is essential for cell homeostasis and growth but lethal if improperly regulated. Transcription of this oncogene is governed by the counterbalancing forces of two proteins on TFIIH—the FUSE binding protein (FBP) and the FBP‐interacting repressor (FIR). FBP and FIR recognize single‐stranded DNA upstream of the P1 promoter, known as FUSE, and influence transcription by oppositely regulating TFIIH at the promoter site. Size exclusion chromatography coupled with light scattering reveals that an FIR dimer binds one molecule of single‐stranded DNA. The crystal structure confirms that FIR binds FUSE as a dimer, and only the N‐terminal RRM domain participates in nucleic acid recognition. Site‐directed mutations of conserved residues in the first RRM domain reduce FIR's affinity for FUSE, while analogous mutations in the second RRM domain either destabilize the protein or have no effect on DNA binding. Oppositely oriented DNA on parallel binding sites of the FIR dimer results in spooling of a single strand of bound DNA, and suggests a mechanism for c‐myc transcriptional control.