2. Academic Validation
  3. The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79

The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79

  • Mol Cell. 2015 Oct 15;60(2):319-27. doi: 10.1016/j.molcel.2015.08.019.
Shoudeng Chen 1,  Ze Yang 2,  Alex W Wilkinson 2,  Aniruddha J Deshpande 3,  Simone Sidoli 4,  Krzysztof Krajewski 5,  Brian D Strahl 5,  Benjamin A Garcia 4,  Scott A Armstrong 3,  Dinshaw J Patel 6,  Or Gozani 7
Affiliations

Affiliations

  • 1 Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • 3 Pediatrics and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • 6 Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: pateld@mskcc.org.
  • 7 Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: ogozani@stanford.edu.
PMID: 26439302 DOI: 10.1016/j.molcel.2015.08.019
Abstract

AF10, a DOT1L cofactor, is required for H3K79 methylation and cooperates with DOT1L in leukemogenesis. However, the molecular mechanism by which AF10 regulates DOT1L-mediated H3K79 methylation is not clear. Here we report that AF10 contains a "reader" domain that couples unmodified H3K27 recognition to H3K79 methylation. An AF10 region consisting of a PHD finger-Zn knuckle-PHD finger (PZP) folds into a single module that recognizes Amino acids 22-27 of H3, and this interaction is abrogated by H3K27 modification. Structural studies reveal that H3 binding triggers rearrangement of the PZP module to form an H3(22-27)-accommodating channel and that the unmodified H3K27 side chain is encased in a compact hydrogen-bond acceptor-lined cage. In cells, PZP recognition of H3 is required for H3K79 dimethylation, expression of DOT1L-target genes, and proliferation of DOT1L-addicted leukemic cells. Together, our results uncover a pivotal role for H3K27-via readout by the AF10 PZP domain-in regulating the cancer-associated Enzyme DOT1L.

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