Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3

Oncogene. 2005 Aug 18;24(35):5401-13. doi: 10.1038/sj.onc.1208714.


The PML gene of acute promyelocytic leukemia (APL) encodes a cell-growth and tumor suppressor. PML localizes to discrete nuclear bodies (NBs) that are disrupted in APL cells, resulting from a reciprocal chromosome translocation t (15;17). Here we show that the nuclear localization of PML is also regulated by SUMO-3, one of the three recently identified SUMO isoforms in human cells. SUMO-3 bears similar subcellular distribution to those of SUMO-1 and -2 in the interphase nuclear body, which is colocalized with PML protein. However, both SUMO-2 and -3 are also localized to nucleoli, a region lacking SUMO-1. Immunoprecipitated PML protein bears SUMO-3 moiety in a covalently modified form, supporting the notion that PML is conjugated by SUMO-3. To determine the functional relevance of SUMO-3 conjugation on PML molecular dynamics, we suppressed SUMO-3 protein expression using a siRNA-mediated approach. Depletion of SUMO-3 markedly reduced the number of PML-containing NBa and their integrity, which is rescued by exogenous expression of SUMO-3 but not SUMO-1 or SUMO-2. The specific requirement of SUMO-3 for PML nuclear localization is validated by expression of SUMO-3 conjugation defective mutant. Moreover, we demonstrate that oligomerization of SUMO-3 is required for PML retention in the nucleus. Taken together, our studies provide first line of evidence showing that SUMO-3 is essential for PML localization and offer novel insight into the pathobiochemistry of APL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • Cell Nucleus / metabolism*
  • Fluorescent Antibody Technique
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Intranuclear Inclusion Bodies / chemistry
  • Intranuclear Inclusion Bodies / metabolism*
  • Leukemia, Promyelocytic, Acute / metabolism
  • Microscopy, Confocal
  • Mutagenesis, Site-Directed
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Promyelocytic Leukemia Protein
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • RNA, Small Interfering
  • SUMO-1 Protein / chemistry
  • SUMO-1 Protein / metabolism
  • Small Ubiquitin-Related Modifier Proteins / chemistry
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*


  • Neoplasm Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • Protein Isoforms
  • RNA, Small Interfering
  • SUMO-1 Protein
  • SUMO2 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human