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 - 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
SN - 1097-2765
VL - 60
SP - 319
EP - 327
JO - Molecular cell
JF - Molecular cell
IS - 2
ER -