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
  • 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: [email protected].
  • 7. Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
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.