Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing

Zhou, Yonggang; Schmitz, Kerstin Maike; Mayer, Christine; Yuan, Xuejun; Akhtar, Asifa; Grummt, Ingrid

doi:10.1038/ncb1914

Cited by 105 publications

(88 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…33,34 Our preliminary data indicate that TTRAP associates to histone deacetylase HDAC1 and HDAC3 and to co-repressor complex Sin3A, and these bindings are enhanced upon proteasome inhibition. All these proteins have been found in the nucleolar proteome.…”

Section: Discussionmentioning

confidence: 82%

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

et al. 2011

View full text Add to dashboard Cite

TRAF and TNF receptor-associated protein (TTRAP) is a multifunctional protein that can act in the nucleus as a 5 0 -tyrosyl DNA phosphodiesterase and in the cytoplasm as a regulator of cell signaling. In this paper we show that in response to proteasome inhibition TTRAP accumulates in nucleolar cavities in a promyelocytic leukemia protein-dependent manner. In the nucleolus, TTRAP contributes to control levels of ribosomal RNA precursor and processing intermediates, and this phenotype is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Our findings suggest a previously unidentified function for TTRAP and nucleolar cavities in ribosome biogenesis under stress. Cell Death and Differentiation (2012) 19, 488-500; doi:10.1038/cdd.2011; published online 16 September 2011 TRAF and TNF receptor-associated protein (TTRAP) is a 5 0 -tyrosyl DNA phosphodiesterase that is required for the repair of topoisomerase2-induced DNA double-strand breaks. 1 It is a member of the endonuclease/exonuclease/ phosphatase family of proteins containing an Mg(2 þ )-dependent apurinic/apyrimidinic endonuclease Ape1-like domain. 2 Various yeast-two hybrid (Y2H) screenings and functional studies have unveiled TTRAP ability to interact with TNF receptors (TNFR) family members and TNFR-associated factors (TRAFs), especially TRAF6. 3 Furthermore, TTRAP was isolated as ETS-associated protein II 4 and as alk4-and smad3-binding protein. 5 Interestingly, TTRAP sequence contains a SUMO-interacting motif (SIM) that is required for its high affinity binding to SUMO-2/3. 6 TTRAP may thus has a role in the cytoplasm as a signaling molecule and in the nucleus as a DNA damage response protein and transcriptional regulator. In this context, its potential interaction with promyelocytic leukemia protein (PML), as previously determined in Y2H, suggests that TTRAP is a PML nuclear bodies (PML-NBs)-associated protein. 7 It remains unclear whether its 5 0 -tyrosyl DNA phosphodiesterase activity may account for all TTRAP biological functions.According to the cellular context, TTRAP may either protect cells from apoptosis or promote death. [8][9][10] When human SH-SY5Y cells are stressed by low doses of proteasome inhibitors, TTRAP is neuroprotective. In these conditions, endogenous TTRAP relocalizes to the cytoplasm and forms aggresome-like inclusions.In this paper we show that in response to high doses of proteasome inhibitors, TTRAP localizes to the nucleolus. This accumulation requires the association to PML-NBs and occurs in nucleolar cavities, a compartment devoid of markers of the 'ribosomal nucleolus'. Lack of TTRAP alters the levels of precursor ribosomal RNA (pre-rRNA) and processing intermediates, suggesting a new role of the PML-NBs-associated protein TTRAP in rRNA biogenesis. This function is dependent on TTRAP SIM motif, but is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Altogether, these data suggest a novel function for TTRAP and nucleolar cavities in controlling rRNA biogenesis in response to proteasome inhibiti...

show abstract

Section: Discussionmentioning

confidence: 82%

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

et al. 2011

View full text Add to dashboard Cite

show abstract

“…2G). While the association of pRNA correlated with TIP5 binding to rDNA (Zhou et al 2009), the binding of TTF-I and pRNA to T 0 were mutually exclusive. TTF-I was associated with chromatin at mid-S phase when no binding of pRNA was observed, whereas in late S phase the level of chromatin-associated pRNA increased and TTF-I binding decreased.…”

Section: Dna:rna Triplexes Target Dnmt3bmentioning

confidence: 94%

Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes

Schmitz¹,

Mayer²,

Postepska³

et al. 2010

Genes Dev.

Self Cite

443

390

View full text Add to dashboard Cite

Noncoding RNAs are important components of regulatory networks controlling the epigenetic state of chromatin. We analyzed the role of pRNA (promoterassociated RNA), a noncoding RNA that is complementary to the rDNA promoter, in mediating de novo CpG methylation of rRNA genes (rDNA). We show that pRNA interacts with the target site of the transcription factor TTF-I, forming a DNA:RNA triplex that is specifically recognized by the DNA methyltransferase DNMT3b. The results reveal a compelling new mechanism of RNA-dependent DNA methylation, suggesting that recruitment of DNMT3b by DNA:RNA triplexes may be a common and generally used pathway in epigenetic regulation.Supplemental material is available at http://www.genesdev.org.Received April 28, 2010; revised version accepted August 26, 2010. Noncoding RNAs (ncRNAs) play a profound and complex role in regulating gene expression (Goodrich and Kugel 2009). While the mechanistic details of how RNA and chromatin are connected remain unclear, there is increasing evidence that epigenetic regulation likely represents a balanced interplay of both RNA and chromatin fields (Bernstein and Allis 2005;Mattick 2009). Previous studies have established that ncRNA plays a key role in epigenetic silencing of rRNA genes. Mammalian genomes contain several clusters of tandemly arrayed rRNA genes (rDNA), of which only a subset is transcribed. Silent rDNA repeats are marked by heterochromatic histone modifications and CpG methylation of the rDNA promoter . The establishment and maintenance of the heterochromatic state is mediated by NoRC (Strohner et al. 2001), a chromatin remodeling complex comprising the ATPase SNF2h and a large subunit, termed TIP5 (TTF-Iinteracting protein #5). NoRC silences rRNA genes by recruiting enzymes that mediate heterochromatin formation and silencing (Zhou et al. 2002;Zhou and Grummt 2005). Transcriptional silencing involves DNA methylation at a critical CpG residue (CpG-133) within the upstream control element (UCE) of the rDNA promoter, thereby impairing binding of the transcription factor UBF and abrogating transcription complex formation . Importantly, NoRC function requires the association of TIP5 with RNA that originates from an RNA polymerase I (Pol I) promoter located in the intergenic spacer ;2 kb upstream of the pre-rRNA transcription start site (Mayer et al. 2006). These intergenic transcripts are of low abundance and usually do not accumulate in vivo because they are rapidly degraded or processed into 150-to 250-nucleotide (nt) RNAs that are shielded from degradation by binding to NoRC. These NoRC-associated transcripts are termed pRNA (for promoter-associated RNA), as their sequence matches the rDNA promoter. TIP5 recognizes the secondary structure of pRNA, and the interaction of TIP5 with pRNA changes the structure of both pRNA and NoRC in an induced fit mechanism (Mayer et al. 2008). Antisensemediated depletion of pRNA leads to nucleoplasmic distribution of NoRC, hypomethylation of rDNA, and enhanced Pol I transcription. ''RNA refeeding'' a...

show abstract

“…The BRD of ATAD2 has been shown to immunoprecipitate histone H3 (K14 ac [68]) but this interaction has not been quantified yet, while the closely homologous KIAA1240 binds to histone H4 (K5 ac [33,69] [70]). Subfamily V of the human BRDs contains the transcriptional repressor tripartite motif-containing 66 (TRIM66) [71], the tripartite motif-containing 33 (TRIM33) [72], the transcriptional regulator transcriptional intermediary factor 1 (TIF1a) [73], the transcriptional regulators nuclear auto-antigen Sp-100 (SP100) [74], nuclear autoantigen Sp-110 (SP110) [75] and SP140 nuclear body protein (SP140) [76] as well as the SP140-like protein (LOC93349), the transcriptional repressor bromodomain adjacent to zinc finger domain 2A (BAZ2A) [77] and the bromodomain adjacent to zinc finger domain 2B (BAZ2B) [78]. The main characteristic of this sub-class of bromodomains is the existence of a PHD/BRD tandem module which seems to be a necessary structural motif for peptide recognition as well as protein stability [73,79].…”

Section: Bromodomain Substratesmentioning

confidence: 99%

The bromodomain interaction module

2012

View full text Add to dashboard Cite

a b s t r a c t e-N-acetylation of lysine residues (K ac ) is one of the most abundant post-translation modifications (PTMs) in the human proteome. In the nucleus, acetylation of histones has been linked to transcriptional activation of genes but the functional consequences of most acetylation events and proteins recruited to these sites remains largely unknown. Bromodomains (BRDs) are small helical interaction modules that specifically recognize acetylation sites in proteins. BRDs have recently emerged as interesting targets for the development of specific protein interaction inhibitors, enabling a novel exiting strategy for the development of new therapies. This review provides an overview over sequence requirements of BRDs, known substrates and the structural mechanisms of specific K ac recognition.

show abstract

Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing

Cited by 105 publications

References 28 publications

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes

The bromodomain interaction module

Contact Info

Product

Resources

About