SUMOylation of the Corepressor N-CoR Modulates Its Capacity to Repress Transcription

Tiefenbach, Jens; Novac, Natalia; Ducasse, Miryam; Eck, Maresa; Melchior, Frauke; Heinzel, Thorsten

doi:10.1091/mbc.e05-07-0610

Cited by 50 publications

(50 citation statements)

References 52 publications

(68 reference statements)

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“…13,15 Other post-transcriptional modifications may also regulate functional N-CoR and SMRT specificity, since it has recently been shown that N-CoR is sumoylated. 23 N-CoR and SMRT exert their function by recruiting repression elements to specific promoters and several transcription factors have been shown to interact with NCoRs such as Nuclear Receptors, RBPjk, p65, MyoD. Although specific functions for different NCoRs are not well characterized and both proteins are ubiquitously expressed, deletion of the N-CoR gene in mice results in an embryonic lethal phenotype indicating that SMRT cannot rescue the lack of this gene.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Cytoplasmic Localization of N-CoR in Colorectal Tumors

Fernández‐Majada

Pujadas²,

Vilardell³

et al. 2007

Cell Cycle

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Section: Discussionmentioning

confidence: 99%

Aberrant Cytoplasmic Localization of N-CoR in Colorectal Tumors

Fernández‐Majada

Pujadas²,

Vilardell³

et al. 2007

Cell Cycle

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“…TIF1␤ Sumoylation, a Prerequisite for Transcriptional RepressionOur functional assays strongly suggest that the transcriptional repression mediated by TIF1␤ requires its post-translational modification by SUMO, an observation also made for other transcriptional regulators such as Sp3, Elk-1, and BKLF transcription factors (38,46,49) or co-regulators such as p300, CtBP, and N-CoR (34,44,87). Reducing the number of TIF1␤ SUMO acceptor sites by mutating single, double, and multiple sumoylation target lysine residues progressively decreased TIF1␤-dependent transcriptional repression to near a basal repressive level.…”

Section: Tif1␤ a Substrate Rich In Lysine Residuesmentioning

confidence: 90%

“…While the vast majority of SUMO target proteins were described to contain one or two SUMO modification sites, TIF1␤ appears as a multiacceptor protein for SUMO such as PML, Daxx, and N-CoR (44,81,82). Interestingly, all TIF1␤ sumoylation sites are positioned in its repressive region which contains a PHD finger and a bromo domain.…”

Section: Tif1␤ a Substrate Rich In Lysine Residuesmentioning

confidence: 99%

Sumoylation of the Transcriptional Intermediary Factor 1β (TIF1β), the Co-repressor of the KRAB Multifinger Proteins, Is Required for Its Transcriptional Activity and Is Modulated by the KRAB Domain

Mascle

Germain-Desprez

Huynh

et al. 2007

Journal of Biological Chemistry

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Small ubiquitin-related modifier (SUMO) has emerged as a key post-translational modulator of protein functions. Here we show that TIF1␤, a developmental regulator proposed to act as a universal co-repressor for the large family of KRAB domaincontaining zinc finger proteins, is a heavily SUMO-modified substrate. A combined analysis of deletion and punctual mutants identified TIF1␤ as a multilysine acceptor for SUMO which specifically targets six lysine residues (Lys 554 , Lys 575 , Lys 676 , Lys 750 , Lys 779 , and Lys 804 ) within the TIF1␤ C-terminal repressive region. Reporter gene assays indicate that TIF1␤ requires SUMO-modification for its repressive activity. Indeed, sumoylation-less mutants failed to recapitulate TIF1␤-dependent repression. TIF1␤ homodimerization properties and interaction with the KRAB domain are preserved in the mutants with lysine to arginine substitutions as confirmed by in vivo bioluminescence resonance energy transfer (BRET). Using histone deacetylase (HDAC) inhibitors, we also demonstrate that TIF1␤ sumoylation is a prerequisite for the recruitment of HDAC and that TIF1␤ SUMO-dependent repressive activity involves both HDAC-dependent and HDAC-independent components. Finally, we report that, in addition to relying on the integrity of its PHD finger and on its self-oligomerization, TIF1␤ sumoylation is positively regulated by its interaction with KRAB domain-containing proteins. Altogether, our results provide new mechanistic insights into TIF1␤ transcriptional repression and suggest that KRAB multifinger proteins not only recruit TIF1␤ co-repressor to target genes but also increase its repressive activity through enhancement of its sumoylation.The transcriptional intermediary factor 1␤ (TIF1␤, 2 KRIP-1, KAP-1, TRIM 28) is an essential developmental regulator belonging to the TIF1 family and is believed to act as the universal transcriptional co-repressor for the large family of vertebrate-specific Krüppel-associated box (KRAB) domain-containing zinc finger transcription factors (1-7). All TIF1 family members (TIF1␣, ␤, ␥, ␦, and bonus) are characterized by an N-terminal tri-partite motif (named TRIM or RBCC) composed of a RING (really interesting new genes) finger followed by two B-boxes and a coiled-coil domain as well as a C-terminal bi-partite motif encompassing a PHD (Plant HomeoDomain) finger and a bromo domain (2, 8 -11). The RBCC motif of TIF1␤ is known to homodimerize and to specifically interact with the KRAB domain of KRAB multifinger proteins (12-14). The TIF1␤ PHD finger and bromo domain were reported to cooperate in transcriptional repression via recruitment of repressive enzymatic activities such as histone deacetylase complexes (NurD/Mi2-␣) and a methyltransferase protein (SETDB1) (15, 16). Moreover, TIF1␤ (like all TIF1 family members) displays the canonical amino acid motif, PXVXL, interacting with HP1 heterochromatin proteins (HP1␣, ␤, and ␥) involved in gene silencing (17)(18)(19). Recently, the TIF1␤/HP1 interaction was shown to be essential for histone modificat...

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“…23). These proteins could themselves be susceptible to SUMO modification as has been shown for Dnmt3A, 24,25 N-CoR, 26 HDACs 1 and -4, 27,28 MCAF1, MBD1, 23 or the reptin remodelling complex. 29 Interestingly, it was shown that histones are prone to SUMO-modification and that sumoylated histones themselves are sumoylated and that sumo-modified histones are involved transcriptional repression.…”

confidence: 95%

SUMO is Growing Senescent

Bischof¹,

Dejean²

2007

Cell Cycle

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SUMOylation of the Corepressor N-CoR Modulates Its Capacity to Repress Transcription

Cited by 50 publications

References 52 publications

Aberrant Cytoplasmic Localization of N-CoR in Colorectal Tumors

Aberrant Cytoplasmic Localization of N-CoR in Colorectal Tumors

Sumoylation of the Transcriptional Intermediary Factor 1β (TIF1β), the Co-repressor of the KRAB Multifinger Proteins, Is Required for Its Transcriptional Activity and Is Modulated by the KRAB Domain

SUMO is Growing Senescent

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