Requirement for Sex Comb on Midleg Protein Interactions in Drosophila Polycomb Group Repression

Peterson, Aidan J.; Mallin, Daniel R.; Francis, Nicole J.; Ketel, Carrie S.; Stamm, Joyce; Voeller, Rochus K.; Kingston, Robert E.; Simon, John

doi:10.1534/genetics.104.027474

Cited by 59 publications

(75 citation statements)

References 72 publications

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“…Long range repression by Scm is dependent on both an intact SAM domain as well as Ph function. In addition, overexpression of an isolated Scm-SAM domain results in a dominant loss of Scm function, suggesting that protein-protein interactions via the SAM module can poison full-length Scm proteins (17). Here, we show that Scm-SAM forms a polymeric structure similar to Ph-SAM and investigate how the two polymeric domains of Ph and Scm can co-polymerize.…”

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confidence: 80%

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Structural Organization of a Sex-comb-on-midleg/Polyhomeotic Copolymer

Kim¹,

Sawaya

Cascio

et al. 2005

Journal of Biological Chemistry

103

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The polycomb group proteins are required for the stable maintenance of gene repression patterns established during development. They function as part of large multiprotein complexes created via a multitude of proteinprotein interaction domains. Here we examine the interaction between the SAM domains of the polycomb group proteins polyhomeotic (Ph) and Sex-comb-on-midleg (Scm). Previously we showed that Ph-SAM polymerizes as a helical structure. We find that Scm-SAM also polymerizes, and a crystal structure reveals an architecture similar to the Ph-SAM polymer. These results suggest that Ph-SAM and Scm-SAM form a copolymer. Binding affinity measurements between Scm-SAM and Ph-SAM subunits in different orientations indicate a preference for the formation of a single junction copolymer. To provide a model of the copolymer, we determined the structure of the Ph-SAM/Scm-SAM junction. Similar binding modes are observed in both homo-and heterocomplex formation with minimal change in helix axis direction at the polymer joint. The copolymer model suggests that polymeric Scm complexes could extend beyond the local domains of polymeric Ph complexes on chromatin, possibly playing a role in long range repression.The PcG 1 proteins form large multiprotein complexes that repress transcription over long distances and maintain repressed states in a stable and heritable manner during embryogenesis, development, and into adulthood (1, 2). PcG mutations result in both developmental defects and cancer (3-5). The formation of such large complex structures requires the precise organization of many proteins of the PcG. Indeed, protein-protein interaction domains are the most common functional motifs that have been identified in the PcG family. Nevertheless, few of these domains have been characterized in detail, and the structural architecture of the resultant protein complexes is largely unknown.One protein-protein interaction domain present in the PcG family is the SAM (sterile alpha motif) domain (often called SPM in PcG literature) found in polyhomeotic (Ph) and Sexcomb-on-midleg (Scm). SAM domains are small, helical protein modules found in proteins with diverse functional roles ranging from receptor tyrosine kinases to transcription factors (6). Unlike many other protein-protein interaction modules that have a common, well defined function such as SH2 domains, SAM domains can play diverse roles. To date, SAM domains are known to form homo-and heterooligomers that can be polymeric (7-9) or have a discrete oligomeric state (10), they can bind to other proteins (11, 12), and they can even bind RNA (13,14).Ph and Scm proteins co-localize on polytene chromosomes (15) and can interact via their SAM domains (15-17). The interaction between Ph and Scm appears to be complex. In addition to binding to each other, the SAM domains of Ph and Scm can also self-associate and thus exist in a higher oligomeric state of their own (8,15,16). Although they appear to work at the same sites, isolation of the soluble form of one PcG protein complex, PR...

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confidence: 80%

“…Ph and Scm proteins co-localize on polytene chromosomes (15) and can interact via their SAM domains (15)(16)(17). The interaction between Ph and Scm appears to be complex.…”

mentioning

confidence: 99%

Structural Organization of a Sex-comb-on-midleg/Polyhomeotic Copolymer

Kim¹,

Sawaya

Cascio

et al. 2005

Journal of Biological Chemistry

103

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“…Several observations suggest that Scm also associates with PRC1 albeit not as a stoichiometric subunit: Biochemical purifications of PRC1 contain substoichiometric amounts of Scm, 52,53 Scm interacts with the PRC1 subunit Ph in vitro 37,54 and can stably assemble into a reconstituted PRC1 complex. 55 However, co-immunoprecipitations failed to confirm a robust interaction between Scm and PRC1 components and the bulk of Scm in embryo extract separates from Ph in gel filtration analysis. 27,55 Nevertheless, Scm repressive activity is sensitive to Ph dosage in reporter gene assays.…”

Section: Mbt Complexesmentioning

confidence: 99%

“…55 However, co-immunoprecipitations failed to confirm a robust interaction between Scm and PRC1 components and the bulk of Scm in embryo extract separates from Ph in gel filtration analysis. 27,55 Nevertheless, Scm repressive activity is sensitive to Ph dosage in reporter gene assays. 38 The exact nature of the PRC1-Scm interaction in vivo remains somewhat enigmatic.…”

Section: Mbt Complexesmentioning

confidence: 99%

Chromatin regulation: How complex does it get?

Meier¹,

Brehm

2014

Epigenetics

100

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“…SCM is required for the recruitment and repressive function of polycomb repressive complex 1 (PRC1) and PRC2 (1), and contains two malignant brain tumor (MBT) repeats, a domain of unknown function (DUF3588), an SPM [also known as sterile α motif (SAM)] domain and two zinc fingers (2,3). SCM exerts a repressive effect on target genes through the actions of MBT and SPM domains, as do other PcG proteins (4,5). Notably, abnormal SCM function may be involved in tissue growth and certain cancers (6).…”

Section: Introductionmentioning

confidence: 99%

Sex comb on midleg like-2 is a novel specific marker for the diagnosis of gastroenteropancreatic neuroendocrine tumors

Yang

Huang

Xiao

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Sex comb on midleg like-2 (SCML2) is a polycomb-group protein that encodes transcriptional repressors essential for appropriate development in the fly and in mammals. On the basis of previous findings, the present study aimed to explore the possibility of developing SCML2 into a new diagnostic marker for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A total of 64 paired GEP-NET tissues and adjacent non-tumorous tissues were obtained from patients who had undergone surgical resection between January 2009 and January 2014, and the expression of SCML2 and two neuroendocrine markers, namely synaptophysin (Syn) and chromogranin A (CgA), in the tissues was assessed by immunohistochemistry. Strong SCML2 staining was observed predominantly in the cell nuclei of GEP-NET tissues, and the overall expression rate and staining intensity of SCML2 were higher than those of Syn or CgA, respectively. Spearman rank correlation analysis demonstrated that SCML2 was not correlated with either Syn or CgA, while the combined detection of SCML2 with Syn or with CgA increased the diagnostic sensitivity to 100%. SCML2 expression in GEP-NETs was associated with several clinicopathological parameters, such as histological type, tumor grade, depth of invasion and clinical stage. Kaplan-Meier survival curves revealed that patients with higher SCML2 expression had lower survival rates than those with lower expression levels, while Cox proportional hazards regression analysis revealed that SCML2 was not an independent prognostic factor for GEP-NET patients. Therefore, SCML2 may have potential as a specific marker for joint use with other markers to improve the diagnostic efficiency of GEP-NETs.

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Requirement for Sex Comb on Midleg Protein Interactions in Drosophila Polycomb Group Repression

Cited by 59 publications

References 72 publications

Structural Organization of a Sex-comb-on-midleg/Polyhomeotic Copolymer

Structural Organization of a Sex-comb-on-midleg/Polyhomeotic Copolymer

Chromatin regulation: How complex does it get?

Sex comb on midleg like-2 is a novel specific marker for the diagnosis of gastroenteropancreatic neuroendocrine tumors

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