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Acute lymphoblastic leukemia

Comment on structural basis of DUX4/IGH-driven transactivation

Leukemia volume 32, pages 2090–2092 (2018)Cite this article

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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].

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References

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Author notes

  1. John K. Lee

    Present address: Bristol-Myers Squibb, Redwood City, CA, 94063, USA

Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA

    Hideki Aihara, Ke Shi & John K. Lee

  2. Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, 55455, USA

    Darko Bosnakovski & Michael Kyba

  3. Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA

    Darko Bosnakovski & Michael Kyba

  4. Faculty of Medical Sciences, University Goce Delcev - Stip, Krste Misirkov b.b, 2000, Stip, Macedonia

    Darko Bosnakovski

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Correspondence to Hideki Aihara.

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Aihara, H., Shi, K., Lee, J.K. et al. Comment on structural basis of DUX4/IGH-driven transactivation. Leukemia 32, 2090–2092 (2018). https://doi.org/10.1038/s41375-018-0217-7

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