Role of SUMO-Interacting Motif in Daxx SUMO Modification, Subnuclear Localization, and Repression of Sumoylated Transcription Factors

Abstract

Small ubiquitin-like modifier (SUMO) modification has emerged as an important posttranslational control of protein functions. Daxx, a transcriptional corepressor, was reported to repress the transcriptional potential of several transcription factors and target to PML oncogenic domains (PODs) via SUMO-dependent interactions. The mechanism by which Daxx binds to sumoylated factors mediating transcriptional and subnuclear compartmental regulation remains unclear. Here, we define a SUMO-interacting motif (SIM) within Daxx and show it to be crucial for targeting Daxx to PODs and for transrepression of several sumoylated transcription factors, including glucocorticoid receptor (GR). In addition, the capability of Daxx SIM to bind SUMO also controls Daxx sumoylation. We further demonstrate that arsenic trioxide-induced sumoylation of PML correlates with a change of endogenous Daxx partitioning from GR-regulated gene promoter to PODs and a relief of Daxx repression on GR target gene expression. Our results provide mechanistic insights into Daxx in SUMO-dependent transcriptional control and subnuclear compartmentalization.

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

“…Moreover, a derepression of c-Myb activity was observed with the A 267 NAA mutant. Because the latter effect resembled that of the SUMO conjugation-disrupting 2KR mutations, we asked whether derepression by the ANAA mutation might be caused by SUMO conjugation being dependent on a functional SIM as previously shown for TDG, Daxx and SP100 (Takahashi et al, 2005;Lin et al, 2006;Knipscheer et al, 2008). The two SIM mutants (A 267 NAA and I 267 NII) were expressed in CV-1 cells in absence or presence of the SUMO E2-conjugating enzyme Ubc9 or the SUMO E3 ligase PIASy, increasing the relative amount of sumoylated c-Myb, and the sumoylation patterns were compared with those of wild type c-Myb (two mono-þ one disumoylated form) and 2KR (no sumoylated forms) ( Figure 4).…”

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

“…Because of the large size of SUMO, lysine SUMOylation can alter a target protein's conformation or modulate its interactions with other cellular proteins in a SUMO-dependent manner. Recent studies show that SUMOylation of transcription factors has a direct role in transcriptional control and subnuclear compartmentalization 44 . Indeed, KAP1 SUMOylation has recently been shown to recruit the SETDB1 histone methyltransferase and the NuRD remodeling complex by binding to SUMO-interacting motifs, leading to chromatin remodeling and modifications at the site of a target gene 33 .…”

In vivo modeling of polysumoylation uncovers targeting of Topoisomerase II to the nucleolus via optimal level of SUMO modification

“…Based on our observations, we can infer the existence of a mechanisms that controls nucleolar localization of a subset of given nuclear proteins by their targeting to the nucleolus via transient polysumoylation and their nucleolar retention via recognition by some SUMO-binding protein(s) residing in the nucleolus. As putative SUMObinding domains have recently been identified (Hecker et al 2006;Lin et al 2006;Kerscher 2007;Sun et al 2007;Uzunova 2007), it is conceivable that some nucleolar proteins may have an ability to serve as receptors for sumoylated proteins, which hence acquire a nucleolarspecific function through such interactions. The experimental approach to modeling polysumoylation in vivo.…”