期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-019-11746-0
关键词
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资金
- National Natural Science Foundation of China [81770142, 81370620, 81570120, 31070645, 81800144, 31800642]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20152504]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institute of Higher Learning
- SMSTC [11JC1407200]
- SME [12ZZ109]
- Program for New Century Excellent Talents in University [NCET-10-9571]
- Samuel Waxman Cancer Research Foundation
ProMyelocyticLeukemia (PML) protein can polymerize into a mega-Dalton nuclear assembly of 0.1-2 mu m in diameter. The mechanism of PML nuclear body biogenesis remains elusive. Here, PMLRBCC is successfully purified. The gel filtration and ultracentrifugation analysis suggest a previously unrecognized sequential oligomerization mechanism via PML monomer, dimer, tetramer and N-mer. Consistently, PML B1-box structure (2.0 angstrom) and SAXS characterization reveal an unexpected networking by W157-, F158- and SD1-interfaces. Structure-based perturbations in these B1 interfaces not only impair oligomerization in vitro but also abolish PML sumoylation and nuclear body biogenesis in HeLaPml-/- cell. More importantly, as demonstrated by in vivo study using transgenic mice, PML-RAR alpha (PR) F158E precludes leukemogenesis. In addition, single cell RNA sequencing analysis shows that B1 oligomerization is an important regulator in PML-RAR alpha-driven transactivation. Altogether, these results not only define a previously unrecognized B1-box oligomerization in PML, but also highlight oligomerization as an important factor in carcinogenesis.
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