Functional significance of SUMO modified transcription factors

My research has focused on the posttranslational modification of proteins by SUMO (small ubiquitin-like modifier) and how SUMO modification affects transcription. The effects of SUMO modification on transcription are largely unknown. A major unanswered question is whether the effect of SUMO modification is unique for each transcription factor or whether SUMO modification may have a common function. It is also unclear how different transcription factors are selectively recognized by the SUMO modification machinery and how recognition is regulated.; The mechanisms underlying the regulation of SUMO modification are poorly understood. Initially, I attempted to understand how SUMO substrates were regulated during the cell cycle. This study lead to the discovery that during the pachytene stage of prophase I SUMO substrates are concentrated in the XY body. The XY body is known for its lack of recombination and transcriptional inactivity. We hypothesized that the localization of SUMO substrates to the XY body was to sequester factors away from active parts of the cell. We demonstrated that the PML nuclear bodies and the XY body possess many of the same proteins suggesting a shared functional significance, possibly regulating transcription.; My work then shifted to characterizing several SUMO modified transcription factors. I examined the effects of SUMO modification on the heat shock transcription factors (HSF1 and HSF2) and the signal transducers and activators of transcription 1 (STAT1). I showed that modification occurred at conserved consensus sequence sites in HSF1, HSF2 and STAT1. Studies examining transcriptional activity of HSF1 revealed for the first time that SUMO modification could regulate the DNA binding activity of transcription factors. Based on these studies, we proposed a model suggesting that stress induced SUMO modification of HSF1 triggers transcription activation. I also demonstrated that the protein inhibitors of activated STAT (PIAS) could inhibit STAT1 mediated transcription independent of SUMO modification of STAT1, even though the PIAS proteins enhanced the SUMO modification of STAT1 by acting as E3 ligases.; My studies demonstrated that SUMO modification could influence transcription factors in a substrate dependant manner by influencing their localization, DNA binding ability or ability to activate transcription.