SUMO modification regulates the transcriptional activity of FLASH

Alm-Kristiansen, Anne Hege; Norman, Ingrid Louise; Matre, Vilborg; Gabrielsen, Odd S.

doi:10.1016/j.bbrc.2009.07.053

Cited by 10 publications

(13 citation statements)

References 23 publications

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“…The SUMO substrate(s) among the several specific and more general transcription factors that regulate coordinated expression of canonical histones remain(s) to be identified (for review, see Marzluff et al 2008). Of note, PIASY was reported to act as a SUMO E3 ligase for CASP8AP2 (also known as FLASH), a processing factor of histone mRNAs, and IRF2, an activator of histone gene promoters, with sumoylation being repressive in both cases (Han et al 2008;Alm-Kristiansen et al 2009). Active sumoylation also appears to occur at Pol IIItranscribed tRNA genes that are strongly enriched for both SUMO and UBC9.…”

Section: Discussionmentioning

confidence: 99%

Sumoylation at chromatin governs coordinated repression of a transcriptional program essential for cell growth and proliferation

et al. 2013

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Despite numerous studies on specific sumoylated transcriptional regulators, the global role of SUMO on chromatin in relation to transcription regulation remains largely unknown. Here, we determined the genome-wide localization of SUMO1 and SUMO2/3, as well as of UBC9 (encoded by UBE2I ) and PIASY (encoded by PIAS4), two markers for active sumoylation, along with Pol II and histone marks in proliferating versus senescent human fibroblasts together with gene expression profiling. We found that, whereas SUMO alone is widely distributed over the genome with strong association at active promoters, active sumoylation occurs most prominently at promoters of histone and protein biogenesis genes, as well as Pol I rRNAs and Pol III tRNAs. Remarkably, these four classes of genes are up-regulated by inhibition of sumoylation, indicating that SUMO normally acts to restrain their expression. In line with this finding, sumoylationdeficient cells show an increase in both cell size and global protein levels. Strikingly, we found that in senescent cells, the SUMO machinery is selectively retained at histone and tRNA gene clusters, whereas it is massively released from all other unique chromatin regions. These data, which reveal the highly dynamic nature of the SUMO landscape, suggest that maintenance of a repressive environment at histone and tRNA loci is a hallmark of the senescent state. The approach taken in our study thus permitted the identification of a common biological output and uncovered hitherto unknown functions for active sumoylation at chromatin as a key mechanism that, in dynamically marking chromatin by a simple modifier, orchestrates concerted transcriptional regulation of a network of genes essential for cell growth and proliferation.[Supplemental material is available for this article.]The post-translational modification by SUMO is an essential regulatory mechanism of protein function involved in most challenges faced by eukaryotic cells (Hay 2005;Geiss-Friedlander and Melchior 2007;Hochstrasser 2009). Higher eukaryotes have three SUMO paralogs, SUMO1, SUMO2, and SUMO3, with SUMO2 and SUMO3 collectively termed SUMO2/3 because of structural and functional differences from SUMO1. Similarly to ubiquitin, SUMO is covalently conjugated to its targets via a three-step process, including unique E1 (SAE1/UBA2), E2 (UBC9 encoded by UBE2I ), and a series of E3 enzymes including the five PIAS members, CBX4, and RANBP2. The SUMO proteases (SENPs) then remove SUMO from its substrates (Yeh 2009).Investigation of numerous sumoylated transcription factors and chromatin-associated proteins reveals that, in most cases, sumoylation is associated with transcriptional repression (Ouyang and Gill 2009). Moreover, important roles for sumoylation were underscored in heterochromatin configuration (Shin et al. 2005;Maison et al. 2011), and sumoylation of core histones was shown to negatively regulate transcription in yeast and human cells (Shiio and Eisenman 2003;Nathan et al. 2006). However a growing body of evidence also links sumoyla...

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Section: Discussionmentioning

confidence: 99%

Sumoylation at chromatin governs coordinated repression of a transcriptional program essential for cell growth and proliferation

et al. 2013

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“…Thus, the precise role of FLASH in apoptosis is still unclear. We note that Ubc9, the SUMO-conjugating enzyme (E2), was identified in addition to FLASH in the initial yeast two-hybrid screen against the procaspase-8 DEDs and that the FLASH SBD itself has also been shown to form a yeast two-hybrid interaction with Ubc9 and PIAS1 (56,58,59). It may not be coincidental that both SUMO1 itself (also known as Sentrin) and TTRAP/TDP2 and Daxx, two SIM-containing proteins, were initially found as death domain-binding proteins also through yeast two-hybrid screens against death receptors Fas/CD95 or TNFR/CD40 (5, 19, 60 -63).…”

Section: Volume 287 • Number 50 • December 7 2012mentioning

confidence: 99%

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search

Sun

Hunter

2012

Journal of Biological Chemistry

111

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Background: Sumoylation is recognized by proteins with SUMO-interacting motifs. Results: SUMO-interacting motifs were identified through a computational string search and validated in SUMO binding assays. Conclusion: Arkadia, FLASH, C5orf25, and SOBP all contain clustered SIMs. Significance: These proteins contain distinct SUMO binding structures responsible for the recognition of diverse forms of sumoylation.

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“…However, it reduces the transactivating function of a FLASH-Gal4 fusion. 31 These results, along with our study, suggest that SUMO modification of FLASH might have pleiotropic species-and cell type-specific functions. ATO treatment results in cell cycle arrest and induction of apoptosis in APL blast through mediating degradation of the oncogenic PML-RARα fusion protein.…”

Section: 25mentioning

confidence: 53%

“…31 Exchange of SUMO acceptor lysine residue 1823 to arginine did not change the localization pattern of human FLASH. However, it reduces the transactivating function of a FLASH-Gal4 fusion.…”

Section: 25mentioning

confidence: 99%