Transcriptional regulation mediated through the conjugation and deconjugation of the small ubiquitin-like modifiers SUMO-1, SUMO-2, and SUMO-3
Abstract
SUMO-1/2/3 are members of the ubiquitin-like family of protein
modifiers. These proteins are covalently attached to numerous proteins in a
directed and controlled manner. SUMO conjugation primarily occurs to
proteins containing an exposed SUMO conjugation motif, (I, V, L, F)KxE,
where x represents any amino acid. SUMO conjugation is controlled by key
enzymes, a SUMO activating enzyme, SAE1/2 and a SUMO conjugating
enzyme, Ubc9, which is responsible for substrate recognition, and the
efficiency of this pathway can be increased by one of many SUMO ligase
enzymes. This modification alters the substrate's characteristics and results in
a change of state, such as stability, localisation, or activity.
p300, a transcriptional co-activator, contains an evolutionary
conserved tandem SUMO modification motif, located in a transcriptional
repression domain. p300 was efficiently conjugated, both in vitro and in vivo,
by SUMO-1/2/3, within this repression domain to both SUMO conjugation
motifs. The SUMO conjugation to p300 correlated with p300 ability to repress
transcription, requiring both SUMO conjugation motifs for full transcription
repression activity. This repression activity was mediated through SUMO
recruitment of histone deacetylase 6. Repression could be alleviated through
co-expression of a SUMO-specific protease thereby suggesting a potential
regulatory mechanism for transcription control of SUMO modified substrates.
Despite utilising the same conjugation machinery, there remained the
potential for distinct roles for the SUMO isoforms. SUMO -2/3, which form a
distinct group from SUMO-1, were shown to preferentially mediate the
transcription repression abilities of a number of known SUMO modifiable
substrates: p300, Elk-1, and SP3. Further differences were observed in the
ability of SUMO-1 and SUMO-2/3 to influence the nuclear organisation of
p80 coilin.
Type
Thesis, PhD Doctor of Philosophy
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