A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules

Metz, Alexandra; Soret, Johann; Vourc’h, Claire; Tazi, Jamal; Jolly, Caroline

doi:10.1242/jcs.01329

Cited by 116 publications

(95 citation statements)

References 47 publications

(62 reference statements)

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“…Noncoding RNAs are also integral components and implicated in the stabilization of several large-scale chromatin protein complexes. For instance, RNA is a known component of sex chromosome dosage compensation complexes in mammals and Drosophila (47), of the yeast telomerase complex (48), the human pericentromeric heterochromatin (16), or more recently, the nuclear stress bodies containing RNA processing factors (49,50). By analogy, noncoding centromeric RNAs may nucleate or serve as a scaffold for chromatin remodelingcontaining complexes at the centromere.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function

Bouzinba-Ségard

Guais

Francastel

2006

Proc. Natl. Acad. Sci. U.S.A.

211

143

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RNAs have been implicated in the assembly and stabilization of large-scale chromatin structures including centromeric architecture; unidentified RNAs are integral components of human pericentric heterochromatin and are required for localization of the heterochromatin protein HP1 to centromeric regions. Because satellite repeats in centromeric regions are known to be transcribed, we assessed a role for noncoding centromeric RNAs in the structure and function of the centromere. We identified minor satellite transcripts of 120 nt in murine cells that localize to centromeres and accumulate upon stress or differentiation. Forced accumulation of 120-nt transcripts leads to defects in chromosome segregation and sister-chromatid cohesion, changes in hallmark centromeric epigenetic markers, and mislocalization of centromere-associated proteins essential for centromere function. These findings suggest that small centromeric RNAs may represent one of many pathways that regulate heterochromatin assembly in mammals, possibly through tethering of kinetochore-and heterochromatin-associated proteins.centromere ͉ centromeric transcripts ͉ kinetochore T he centromere is a highly specialized structure needed for faithful chromosome segregation during cell division and correct inheritance of genetic information (1). Centromeric regions provide an anchor point for the spindle apparatus, which pulls the separating chromosomes to opposite poles of the dividing cell. In addition, centromeres ensure that sister chromatids are kept together until the appropriate point in the division process.In the absence of conserved DNA sequences among species, two features are considered as a hallmark for centromeric regions, i.e., deposition of the histone H3 variant CENP-A (2, 3) and the constitutively heterochromatic nature of the region associated with the presence of long tandem repeats of short DNA sequences (4, 5). The mouse genome contains two classes of centromeric repetitive sequences, termed major and minor satellites, organized in largely uninterrupted blocks of tandem repeats. Cytological detection of these clusters shows distinct localization, major satellites being associated with pericentromeric regions, whereas minor satellites were detected at the primary constriction of condensed mitotic chromosomes (6, 7). The nature of protein complexes recruited to these satellite repeats also appears to be distinct. The constituents of the kinetochore are recruited, most directly by CENP-A, to minor satellites in a hierarchical and dynamic manner over the progression of the cell cycle (8), whereas heterochromatinassociated proteins, including the heterochromatin protein 1 (HP1), have been shown to mainly concentrate at pericentromeric regions (9). The constitutive heterochromatic state generally includes several typical epigenetic marks such as methylation of DNA (10) and methylation of the lysine 9 of histone H3 (11). These marks are, in turn, responsible for the binding of methyl-DNA-binding proteins and HP1 respectively (12-15).Other mechani...

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Section: Discussionmentioning

confidence: 99%

Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function

Bouzinba-Ségard

Guais

Francastel

2006

Proc. Natl. Acad. Sci. U.S.A.

211

143

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“…This recruitment is mediated by their interaction with stress-induced satellite III (SatIII) transcripts in heatshocked human cultured cells, consequently altering alternative splicing profiles (56,57).…”

Section: Post-translational Modifications Of Sr Proteins: Above and Bmentioning

confidence: 99%

Regulating the regulators: Serine/arginine‐rich proteins under scrutiny

et al. 2012

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SummarySerine/arginine-rich (SR) proteins are among the most studied splicing regulators. They constitute a family of evolutionarily conserved proteins that, apart from their initially identified and deeply studied role in splicing regulation, have been implicated in genome stability, chromatin binding, transcription elongation, mRNA stability, mRNA export and mRNA translation. Remarkably, this list of SR protein activities seems far from complete, as unexpected functions keep being unraveled. An intriguing aspect that awaits further investigation is how the multiple tasks of SR proteins are concertedly regulated within mammalian cells. In this article, we first discuss recent findings regarding the regulation of SR protein expression, activity and accessibility. We dive into recent studies describing SR protein auto-regulatory feedback loops involving different molecular mechanisms such as unproductive splicing, microRNA-mediated regulation and translational repression. In addition, we take into account another step of regulation of SR proteins, presenting new findings about a variety of post-translational modifications by proteomics approaches and how some of these modifications can regulate SR protein sub-cellular localization or stability. Towards the end, we focus in two recently revealed functions of SR proteins beyond mRNA biogenesis and metabolism, the regulation of micro-RNA processing and the regulation of small ubiquitin-like modifier (SUMO) conjugation.

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“…Considering that (i) SF2/ASF shifts its subnuclear localization in response to heat shock from splicing speckles to nSBs in an RRM2-dependent manner (17,18), and (ii) nSBs are known to recruit heat-shock transcription factors, as well as a subset of pre-mRNA processing factors (47) leading to changes in splicing patterns (48), we asked whether nSBs are sites of SUMO-conjugated proteins. Upon heat shock, Sam68, an RNA processing factor and a hallmark of nSBs (47)(48)(49), colocalized with wild-type GFP-SUMO1 but not with a mutant that is unable to conjugate to target proteins [GFP-SUMO1(GA)] (50) (Fig.…”

Section: Sf2/asf Interacts With Ubc9 and Stimulates Sumoylation Of Spmentioning

confidence: 99%

“…Splicing factor 2/alternative splicing factor [SF2/ASF, recently renamed SRSF1 (14)] is a prototypical member of the SR protein family (15,16). Its second RRM (RRM2) is required for translation regulation via mammalian target of rapamycin binding (5) and for SF2/ASF recruitment to nuclear stress bodies (nSBs) upon heat shock (17,18).…”

mentioning

confidence: 99%

The serine/arginine-rich protein SF2/ASF regulates protein sumoylation

Pelisch

Gerez

Druker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Protein modification by conjugation of small ubiquitin-related modifier (SUMO) is involved in diverse biological functions, such as transcription regulation, subcellular partitioning, stress response, DNA damage repair, and chromatin remodeling. Here, we show that the serine/arginine-rich protein SF2/ASF, a factor involved in splicing regulation and other RNA metabolism-related processes, is a regulator of the sumoylation pathway. The overexpression of this protein stimulates, but its knockdown inhibits SUMO conjugation. SF2/ASF interacts with Ubc9 and enhances sumoylation of specific substrates, sharing characteristics with already described SUMO E3 ligases. In addition, SF2/ASF interacts with the SUMO E3 ligase PIAS1 (protein inhibitor of activated STAT-1), regulating PIAS1-induced overall protein sumoylation. The RNA recognition motif 2 of SF2/ASF is necessary and sufficient for sumoylation enhancement. Moreover, SF2/ASF has a role in heat shock-induced sumoylation and promotes SUMO conjugation to RNA processing factors. These results add a component to the sumoylation pathway and a previously unexplored role for the multifunctional SR protein SF2/ASF. posttranslational modification | splicing factor | RNA processing | E3 ligase S er/Arg-rich (SR) proteins were first described as regulators of both constitutive and alternative splicing (1, 2). They are characterized by a modular structure consisting of a C terminal domain-rich in arginine and serine dipeptides (RS domain) and one or two N-terminal RNA-recognition motifs (RRMs) (1). Although RS domains were first identified as protein-protein interaction platforms, it has been shown that they contact the RNA directly at the splicing branch point and the 5′ splice site (3, 4). In addition, RRMs, originally reported to contact the RNA, were shown to mediate protein-protein interactions (5). The function of SR proteins exceeds splicing regulation (2, 6). They regulate transcription (7), mRNA export (8), mRNA stability (9, 10), translation (5, 11), and genome stability (12, 13). Splicing factor 2/alternative splicing factor [SF2/ASF, recently renamed SRSF1 (14)] is a prototypical member of the SR protein family (15, 16). Its second RRM (RRM2) is required for translation regulation via mammalian target of rapamycin binding (5) and for SF2/ASF recruitment to nuclear stress bodies (nSBs) upon heat shock (17, 18).Small ubiquitin-related modifier (SUMO) is a transient and reversible posttranslational protein modifier (19)(20)(21). SUMO proteins (SUMO1 to -4) are expressed in an immature proform that carries a C-terminal stretch of variable length. Removal of this C-terminal extension by SUMO-specific proteases (SENPs) leaves an invariant Gly-Gly motif that marks the C terminus of the mature protein (22). The steps involved in the SUMO pathway resemble those of the ubiquitin pathway (23). The first step is the ATP-dependent activation of a mature SUMO protein by the SUMO-specific E1 activating enzyme heterodimer (SAE I/SAE II in mammals). Next, SUMO is transferred from ...

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A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules

Cited by 116 publications

References 47 publications

Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function

Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function

Regulating the regulators: Serine/arginine‐rich proteins under scrutiny

The serine/arginine-rich protein SF2/ASF regulates protein sumoylation

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