| 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. [RAD21_HUMAN] Cornelia de Lange syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1]
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. [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.[2] [3]
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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, Monnich M, Yan Y, Xu W, Gil-Rodriguez MC, Clark D, Hakonarson H, Halbach S, Michelis LD, Rampuria A, Rossier E, Spranger S, Van Maldergem L, Lynch SA, Gillessen-Kaesbach G, Ludecke HJ, Ramsay RG, McKay MJ, Krantz ID, Xu H, Horsfield JA, Kaiser FJ. RAD21 mutations cause a human cohesinopathy. Am J Hum Genet. 2012 Jun 8;90(6):1014-27. doi: 10.1016/j.ajhg.2012.04.019. Epub, 2012 May 24. PMID:22633399 doi:http://dx.doi.org/10.1016/j.ajhg.2012.04.019
- ↑ Pati D, Zhang N, Plon SE. Linking sister chromatid cohesion and apoptosis: role of Rad21. Mol Cell Biol. 2002 Dec;22(23):8267-77. PMID:12417729
- ↑ Chen F, Kamradt M, Mulcahy M, Byun Y, Xu H, McKay MJ, Cryns VL. Caspase proteolysis of the cohesin component RAD21 promotes apoptosis. J Biol Chem. 2002 May 10;277(19):16775-81. Epub 2002 Mar 1. PMID:11875078 doi:http://dx.doi.org/10.1074/jbc.M201322200
- ↑ 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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