Comment on structural basis of DUX4/IGH-driven transactivation

Hideki, Aihara and Ke , Shi and John , K. Lee and Darko, Bosnakovski and Michael, Kyba (2018) Comment on structural basis of DUX4/IGH-driven transactivation. Leukemia.

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In a recent issue of Leukemia, Dong et al. reported the crystal structure of an isolated second homeodomain of human DUX4 (DUX4HD2) bound to a double-stranded DNA fragment (strand-1: 5’-TTCTAATCTAATCX-3’, X=A according to Materials and methods of the original paper[1], annealed with strand-2: 5’-AAGATTAGATTAGT-3’, whereas the sequence record of PDB entry 5z2t shows X=TT. We also note that 5’-TGATTAGATTAGAA-3’ in Materials and methods of the original paper is the reverse sequence of ‘strand-2’ above, which is from the PDB.) containing the sequence that authors refer to as the DUX4 responsive element (DRE), 5’-TAATCTAAT-3’ [1]. The reported structure consisted of two molecules of DUX4HD2 bound to DNA in a head-to-tail arrangement, with each DUX4HD2 recognizing a TAAT motif on the same strand. We were surprised by this configuration, because the DUX4 recognition sequence as defined by ChIP-seq[2, 3] and by mutagenesis[4] is actually 11-nucleotide (nt) long, not 9 nt, namely, 5’-TAATCTAATCA-3’. The terminal CA nucleotides are among the most highly conserved, but an explanation for their necessity is not provided by the structure presented. An additional curiosity was the fact that the apparently critical TAAT sequences are not present in the mouse Dux consensus sequence, which nevertheless has many residues in common with that of human DUX4, and also includes a strongly conserved CA at positions 10 and 11: 5’-TGATTCAATCA-3’ [5, 6].

Item Type: Article
Subjects: Medical and Health Sciences > Basic medicine
Divisions: Faculty of Medical Science
Depositing User: Darko Bosnakovski
Date Deposited: 04 Feb 2019 09:06
Last Modified: 04 Feb 2019 09:06

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