TY - JOUR
T1 - The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79
AU - Chen, Shoudeng
AU - Yang, Ze
AU - Wilkinson, Alex W.
AU - Deshpande, Aniruddha J.
AU - Sidoli, Simone
AU - Krajewski, Krzysztof
AU - Strahl, Brian D.
AU - Garcia, Benjamin A.
AU - Armstrong, Scott A.
AU - Patel, Dinshaw J.
AU - Gozani, Or
N1 - Funding Information:
We thank S. Blacklow for the T-REx U2OS cells. This work was supported in part by grants from the Leukemia and Lymphoma Society and STARR Foundation to D.J.P. and from the NIH to O.G. (R01 GM079641), S.A.A. (CA66996 and CA176745), B.A.G. (GM110174 and AI118891), and B.D.S. (GM110058). A.W.W. was supported by an NIH training grant (T32 GM007276). S.A.A. is a consultant for Epizyme. O.G. and B.D.S. are cofounders of EpiCypher.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/10/15
Y1 - 2015/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84944891723&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2015.08.019
DO - 10.1016/j.molcel.2015.08.019
M3 - Article
C2 - 26439302
AN - SCOPUS:84944891723
VL - 60
SP - 319
EP - 327
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 2
ER -