The PZP domain of AF10 senses unmodified H3K27 to regulate DOT1L-mediated methylation of H3K79 Journal Article

   

Authors:	Chen, S.; Yang, Z.; Wilkinson, A. W.; Deshpande, A. J.; Sidoli, S.; Krajewski, K.; Strahl, B. D.; Garcia, B. A.; Armstrong, S. A.; Patel, D. J.; Gozani, O.
Article Title:	The PZP domain of AF10 senses unmodified H3K27 to regulate DOT1L-mediated methylation of H3K79
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. © 2015 Elsevier Inc.
Journal Title:	Molecular Cell
Volume:	60
Issue:	2
ISSN:	1097-2765
Publisher:	Cell Press
Date Published:	2015-10-15
Start Page:	319
End Page:	327
Language:	English
DOI:	10.1016/j.molcel.2015.08.019
PROVIDER:	scopus
PMCID:	PMC4609290
PUBMED:	26439302
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84944891723&partnerID=40&md5=ad1b22b6aea7e9cf8937affcc006a6d7
Notes:	Export Date: 2 November 2015 -- Source: Scopus

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