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| | <StructureSection load='6rrc' size='340' side='right'caption='[[6rrc]], [[Resolution|resolution]] 2.37Å' scene=''> | | <StructureSection load='6rrc' size='340' side='right'caption='[[6rrc]], [[Resolution|resolution]] 2.37Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6rrc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RRC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RRC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6rrc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RRC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RRC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.37Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STAG1, SA1, SCC3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rrc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rrc OCA], [http://pdbe.org/6rrc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rrc RCSB], [http://www.ebi.ac.uk/pdbsum/6rrc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rrc ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6rrc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rrc OCA], [https://pdbe.org/6rrc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rrc RCSB], [https://www.ebi.ac.uk/pdbsum/6rrc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rrc ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/STAG1_HUMAN STAG1_HUMAN]] STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/RAD21_HUMAN RAD21_HUMAN]] Cornelia de Lange syndrome. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:22633399</ref> | + | [https://www.uniprot.org/uniprot/STAG1_HUMAN STAG1_HUMAN] STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/STAG1_HUMAN STAG1_HUMAN]] Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. [[http://www.uniprot.org/uniprot/RAD21_HUMAN RAD21_HUMAN]] Cleavable component of the cohesin complex, involved in chromosome cohesion during cell cycle, in DNA repair, and in apoptosis. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At metaphase-anaphase transition, this protein is cleaved by separase/ESPL1 and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Also plays a role in apoptosis, via its cleavage by caspase-3/CASP3 or caspase-7/CASP7 during early steps of apoptosis: the C-terminal 64 kDa cleavage product may act as a nuclear signal to initiate cytoplasmic events involved in the apoptotic pathway.<ref>PMID:12417729</ref> <ref>PMID:11875078</ref> | + | [https://www.uniprot.org/uniprot/STAG1_HUMAN STAG1_HUMAN] Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Edwards A]] |
| - | [[Category: Edwards, A]] | + | [[Category: Gileadi O]] |
| - | [[Category: Gileadi, O]] | + | [[Category: Katis VL]] |
| - | [[Category: Katis, V L]] | + | [[Category: Newman JA]] |
| - | [[Category: Newman, J A]] | + | [[Category: Von Delft F]] |
| - | [[Category: Chromosome segregation]] | + | |
| - | [[Category: Cohesin]]
| + | |
| - | [[Category: Gene regulation]]
| + | |
| - | [[Category: Sa-1]]
| + | |
| Structural highlights
Disease
STAG1_HUMAN STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
STAG1_HUMAN Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.
Publication Abstract from PubMed
The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1 To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2-wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.
STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers.,van der Lelij P, Newman JA, Lieb S, Jude J, Katis V, Hoffmann T, Hinterndorfer M, Bader G, Kraut N, Pearson MA, Peters JM, Zuber J, Gileadi O, Petronczki M Life Sci Alliance. 2020 May 28;3(7). pii: 3/7/e202000725. doi:, 10.26508/lsa.202000725. Print 2020 Jul. PMID:32467316[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ van der Lelij P, Newman JA, Lieb S, Jude J, Katis V, Hoffmann T, Hinterndorfer M, Bader G, Kraut N, Pearson MA, Peters JM, Zuber J, Gileadi O, Petronczki M. STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers. Life Sci Alliance. 2020 May 28;3(7). pii: 3/7/e202000725. doi:, 10.26508/lsa.202000725. Print 2020 Jul. PMID:32467316 doi:http://dx.doi.org/10.26508/lsa.202000725
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