p53 sumoylation: mechanistic insights from reconstitution studies.
Sumoylation represents a cascade of enzymatic reactions mediated by SUMO-activating enzyme (SAE1/SAE2 heterodimer), SUMO-conjugating enzyme Ubc9, and SUMO E3 ligases that include five protein inhibitors of activated STATs (PIAS1, PIAS3, PIASy, PIASxalpha and PIASxbeta), and culminates in the formation of an isopeptide bond between the C-terminal glycine of a small ubiquitin-related modifier (SUMO) and the lysine residue of a protein substrate. Conjugation of a SUMO moiety, ranging from 92 (for SUMO-2) to 97 (for SUMO-1) amino acids, not only increases the molecular size but also alters the property and function of the modified protein. Although sumoylation has been observed with many cellular proteins and the majority of transcription factors including the p53 tumor suppressor, this covalent modification is normally detectable only in a small population, often less than 5%, of a given substrate in vivo. This low abundance of SUMO-modified proteins, due to the presence of sentrin/SUMO-specific proteases (SENPs) that actively cleave the reversible SUMO linkage, has posed a challenge to define the biological effect of SUMO in living cells. Nevertheless, the recent development of reconstituted modification and chromatin-dependent transcription assays has provided unique insights into the molecular action of SUMO in modifying protein function. The availability of these reconstitution systems has unraveled the interplay between sumoylation and acetylation in regulating the DNA binding and transcriptional activity of p53 tetramers and further allow the identification of transcriptional corepressors, such as mSin3A, CoREST1/LSD1 and Mi-2/NuRD implicated in SUMO-dependent gene silencing events.
Wu
Shwu-Yuan
SY
Simmons Comprehensive Cancer Center and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Chiang
Cheng-Ming
CM
D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D011485:Protein Binding; D025842:SUMO-1 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002843:Chromatin; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53