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  • Sumoylation of transcription factors has been generally link

    2021-11-26

    Sumoylation of transcription factors has been generally linked to transcriptional repression and, in a few cases, to transcriptional activation [60] Accumulating evidence implies that corepressor complex subunits, including CoREST, CtBP, Daxx, NCoR1, SMRT and histone deacetylase complexes (HDACs), preferentially associate with DNA-bound, sumoylated transcription factors [39,[61], [62], [63], [64]]. For example, GR sumoylation recruits the SMRT/NCoR1-HDAC3 repressive complex [64] and/or corepressor Daxx [39] to a subset of GR target genes, in which SMRT, NCoR1 and Daxx are bound to sumoylated GR through their SIMs. Notably, recent studies have employed genome-wide approaches to identify genes that are differentially regulated by wild type and SUMO-deficient hormone receptors including AR, GR and PR. Palvimo's research group reported that the sumoylation does not simply repress the AR and GR activity on all target genes, but that this modification regulates the receptor's TH588 australia occupancy and function in a target gene selective manner [65,66]. Consistently, sumoylation of PR was reported to regulate global gene expression by altering PR transcriptional activity and promoter selectivity [67,68]. These studies imply that sumoylation may influence the receptors target-locus selection via regulating interactions with other cofactors. Our study indicates that FAF1/SIMs mediate SUMO-dependent transcriptional repression of the MR, suggesting that FAF1 may be an important factor in mediating SUMO-dependent transcriptional repression. It is possible that the repressive actions of FAF1 could result from a direct effect on MR, but also through indirect mechanisms on its associated coregulators. Our findings emphasize the role of SUMO modifications as a crucial step for the regulation of MR function. Further studies are needed to elucidate the dynamics and molecular mechanisms involved in MR-mediated transcription activation. To date, several MR-associated corepressors have been identified, such as the widely repressive NCoR and SMRT; the histone chaperone, Daxx; and the SUMO E3 ligase, PIAS1. Consensus motifs, the “CoRNR box” (I/L-x-x-I/V-I), which are interaction interfaces between corepressors and NRs, have been described for NCoR, SMRT, and PIAS1 [22,23]. Of interest, several NR co-repressors also contain one or more functional SIMs, including the NCoR, SMRT, PIAS1, and Daxx [32,39,64]. Also, in the present study, three putative CoRNR boxes were identified for FAF1 (Supplementary Fig. S1). However, mutation of all three CoRNR box motifs did not alter FAF1's repressive effects, suggesting that other functional domains, more likely the SIMs, are involved in repressing the function on the MR. Furthermore, several recent studies provided new insights into SUMO-ubiquitin hybrid chain signaling, with important implications for genome maintenance. It is noteworthy that SUMO-ubiquitin hybrid chains are recognized as distinct entities by receptor proteins containing tandem SUMO- and ubiquitin-interacting motifs (tSIM-UIMs) that were characterized as “SUMO-Ub chain receptors”, and yet most of them are DNA repair factors. For example, RAP80, a subunit of the BRCA1-A complex, contains a tandem SIM-UIM-UIM motif that binds to both SUMO2 and Ub Lys-63 conjugates formed at sites of DNA damage [69,70]. Based on these findings, it is intriguing to speculate that the tSIM-UIMs in many multifunctional proteins may engage in interactions with sumoylated and ubiquitylated partners, thereby providing a widespread mechanism to help direct the protein to differential responses. Given that FAF1 was postulated to be a scaffolding protein which contains a UBA and a UBX domain, our new findings open the possibility that FAF1 may also function as a SUMO-Ub chain receptor and interacts with different sumoylated and/or ubiquitinated proteins. Thus, more work is required to clarify how the UBA, UBX, and SIM domains are regulated and differentially contribute to FAF1-mediated cell apoptosis and/or protein degradation.