Abstract
Metastasis tumor antigen 1 (MTA1), a component of the Mi-2·nucleosome remodeling and deacetylase complex, plays a crucial role in gene transcription, but the mechanism involved remains largely unknown. Here, we report that MTA1 is a substrate for small ubiquitin-related modifier 2/3 (SUMO2/3) in vivo. Protein inhibitor of activated STAT (PIAS) proteins enhance SUMOylation of MTA1 and may participate in paralog-selective SUMOylation, whereas sentrin/SUMO-specific protease 1 (SENP1) and 2 may act as deSUMOylation enzymes for MTA1. Moreover, MTA1 contains a functional SUMO-interacting motif (SIM) at its C terminus, and SIM is required for the efficient SUMOylation of MTA1. SUMO conjugation on Lys-509, which is located within the SUMO consensus site, together with SIM synergistically regulates the co-repressor activity of MTA1 on PS2 transcription, probably by recruiting HDAC2 onto the PS2 promoter. Interestingly, MTA1 may up-regulate the expression of SUMO2 via interaction with RNA polymerase II and SP1 at the SUMO2 promoter. These findings not only provide novel mechanistic insights into the regulation of the transcriptional repressor function of MTA1 by SUMOylation and SIM but also uncover a potential function of MTA1 in modulating the SUMOylation pathway.
Highlights
The mechanism by which Metastasis tumor antigen 1 (MTA1) modulates gene repression remains largely unknown
MTA1 up-regulates the expression of SUMO2
MTA1 Can Be SUMOylated—While searching for the potential small ubiquitin-related modifier (SUMO) consensus site in MTA1 (SUMOsp2.0), we found that human MTA1 contains only one highly conserved SUMO consensus site across species, IKAE, which is located outside all functional domains (Fig. 1A)
Summary
The mechanism by which MTA1 modulates gene repression remains largely unknown. Results: SUMOylated Lys-509 in conjunction with SIM is involved in MTA1-mediated repression of its target gene PS2, probably by recruiting HDAC2. 2 The abbreviations used are: SUMO, small ubiquitin-related modifier; SIM, SUMO-interacting motif; MTA1, metastasis tumor antigen 1; PIAS, protein inhibitor of activated STAT; SENP, sentrin/SUMO-specific protease; Ni-NTA, nickel-nitrilotriacetic acid; NuRD, nucleosome remodeling and deacetylase; ERE, estrogen-responsive element; AAA, triple mutant I711A/V712A/ I713A; MEF, mouse embryonic fibroblast; Pol II, RNA polymerase II. These findings suggest a synergistic regulatory mechanism of SUMO modification and SIM in MTA1-mediated gene transcription and reveal a possible function of MTA1 in regulating the SUMOylation pathway
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