Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2.
Sumoylation serves to control key cellular functions, but the regulation of SUMO E3 ligase activity is largely unknown. Here we show that the polycomb group protein Pc2 binds to and colocalizes with homeodomain interacting protein kinase 2 (HIPK2) and serves as a SUMO E3 ligase for this kinase. DNA damage-induced HIPK2 directly phosphorylates Pc2 at multiple sites, which in turn controls Pc2 sumoylation and intranuclear localization. Inducible phosphorylation of Pc2 at threonine 495 is required for its ability to increase HIPK2 sumoylation in response to DNA damage, thereby establishing an autoregulatory feedback loop between a SUMO substrate and its cognate E3 ligase. Sumoylation enhances the ability of HIPK2 to mediate transcriptional repression, thus providing a mechanistic link for DNA damage-induced transcriptional silencing.
Roscic
Ana
A
Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany.
Möller
Andreas
A
Calzado
Marco A
MA
Renner
Florian
F
Wimmer
Verena C
VC
Gresko
Ekaterina
E
Lüdi
Katharina Schmid
KS
Schmitz
M Lienhard
ML
D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000032:analysis; D006801:Humans; D008025:Ligases; D010766:Phosphorylation; D063146:Polycomb-Group Proteins; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000032:analysis; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D063146:Polycomb-Group Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D025842:SUMO-1 Protein; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D008025:Ligases; C570427:CBX4 protein, human