The human EKC/KEOPS complex is recruited to Cullin2 ubiquitin ligases by the human tumour antigen PRAME.
The human tumour antigen PRAME (preferentially expressed antigen in melanoma) is frequently overexpressed during oncogenesis, and high PRAME levels are associated with poor clinical outcome in a variety of cancers. However, the molecular pathways in which PRAME is implicated are not well understood. We recently characterized PRAME as a BC-box subunit of a Cullin2-based E3 ubiquitin ligase. In this study, we mined the PRAME interactome to a deeper level and identified specific interactions with OSGEP and LAGE3, which are human orthologues of the ancient EKC/KEOPS complex. By characterizing biochemically the human EKC complex and its interactions with PRAME, we show that PRAME recruits a Cul2 ubiquitin ligase to EKC. Moreover, EKC subunits associate with PRAME target sites on chromatin. Our data reveal a novel link between the oncoprotein PRAME and the conserved EKC complex and support a role for both complexes in the same pathways.
Department of Molecular Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
Adalberto
A
Costessi
Nawel
N
Mahrour
Vikram
V
Sharma
Rieka
R
Stunnenberg
Marieke A
MA
Stoel
Esther
E
Tijchon
Joan W
JW
Conaway
Ronald C
RC
Conaway
Hendrik G
HG
Stunnenberg
D000951:Antigens, Neoplasm / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D011485:Protein Binding; D021381:Protein Transport; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
D000951:Antigens, Neoplasm; C105153:CUL2 protein, human; D044842:Cullin Proteins; C509947:KEOPS complex, S cerevisiae; C404944:PRAME protein, human; D029701:Saccharomyces cerevisiae Proteins