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Cohesin Mutations in Cancer: Emerging Therapeutic Targets

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Cohesin Mutations in Cancer: Emerging Therapeutic Targets International Journal of Molecular Sciences Review Cohesin Mutations in Cancer: Emerging Therapeutic Targets Jisha Antony 1,2,*, Chue Vin Chin 1 and Julia A. Horsfield 1,2,3,* 1 Department of Pathology, Otago Medical School, University of Otago, Dunedin 9016, New Zealand; [email protected] 2 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand 3 Genetics Otago Research Centre, University of Otago, Dunedin 9016, New Zealand * Correspondence: [email protected] (J.A.); julia.horsfi[email protected] (J.A.H.) Abstract: The cohesin complex is crucial for mediating sister chromatid cohesion and for hierarchal three-dimensional organization of the genome. Mutations in cohesin genes are present in a range of cancers. Extensive research over the last few years has shown that cohesin mutations are key events that contribute to neoplastic transformation. Cohesin is involved in a range of cellular processes; therefore, the impact of cohesin mutations in cancer is complex and can be cell context dependent. Candidate targets with therapeutic potential in cohesin mutant cells are emerging from functional studies. Here, we review emerging targets and pharmacological agents that have therapeutic potential in cohesin mutant cells. Keywords: cohesin; cancer; therapeutics; transcription; synthetic lethal 1. Introduction Citation: Antony, J.; Chin, C.V.; Genome sequencing of cancers has revealed mutations in new causative genes, includ- Horsfield, J.A. Cohesin Mutations in ing those in genes encoding subunits of the cohesin complex. Defects in cohesin function Cancer: Emerging Therapeutic from mutation or amplifications has opened up a new area of cancer research to which Targets. Int. J. Mol. Sci. 2021, 22, 6788. several groups have contributed and provided insights into its impact and therapeutic https://doi.org/10.3390/ijms 22136788 potential. Here, we review underlying pathways that are dysregulated in cohesin mu- tant cancers and discuss some of the emerging targets that could have future therapeutic Academic Editor: Nikolai A. Barlev potential. 2. Cohesin Structure and Dynamics Received: 12 May 2021 Accepted: 18 June 2021 Cohesin is a highly conserved ATPase complex in vertebrates best known for its Published: 24 June 2021 canonical role in establishing sister chromatid cohesion during cell division [1–3]. The mitotic cohesin complex forms a ring-shaped structure that comprises four core subunits: Publisher’s Note: MDPI stays neutral RAD21, SMC3, SMC1A and STAG1/2 (Figure1A) [ 2,4]. Chromatin association of cohesin with regard to jurisdictional claims in is a dynamic process that is regulated by several cofactors (Figure1). Cohesin is loaded published maps and institutional affil- onto chromatin through the action of NIPBL-MAU2 [5] and unloaded by association with iations. WAPL-PDS5A/B [6,7]. These loading and unloading processes balance the amount of cohesin on chromatin for correct chromosome structure and function [7–10]. During DNA replication in S phase, sister chromatid cohesion is established via acetyl- transferases ESCO1/ESCO2 that acetylate SMC3 (Figure1B) [ 11–14], a process that requires Copyright: © 2021 by the authors. the STAG2 subunit [15]. Acetylated SMC3 recruits Sororin to PDS5 and displaces WAPL to Licensee MDPI, Basel, Switzerland. prevent unloading [16,17]. In prophase, most cohesin is unloaded following phosphoryla- This article is an open access article tion of STAG by Polo-like kinase 1 (PLK1), phosphorylation of Sororin by Aurora Kinase distributed under the terms and B and Cyclin-dependent kinase 1 (CDK1), which causes Sororin to dissociate from PDS5 conditions of the Creative Commons and restores PDS5-WAPL [17–20]. However, centromeric cohesion is maintained by the Attribution (CC BY) license (https:// counteracting activity of Shugoshin 1 (SGO1) and Protein Phosphatase 2A (PP2A) [21–23]. creativecommons.org/licenses/by/ At anaphase, centromeric cohesin is removed via enzymatic cleavage of RAD21 by sep- 4.0/). Int. J. Mol. Sci. 2021, 22, 6788. https://doi.org/10.3390/ijms22136788 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 24 Int. J. Mol. Sci. 2021, 22, 6788 2 of 23 of RAD21 by separase [24]. Unloaded cohesin complexes undergo deacetylation of the SMC3 subunit by HDAC8 and, then, can be reused [25] (cohesin dynamics reviewed in arase [24]. Unloaded cohesin complexes undergo deacetylation of the SMC3 subunit by ref [26]). HDAC8 and, then, can be reused [25] (cohesin dynamics reviewed in ref [26]). Figure 1. A Figure 1. (A() Schematic) Schematic of of the the cohesin cohesin complex. complex. Cohesin Cohesin loading loading and and unloading unloading onto onto chromosomes chromosomes during during cell cell cycle cycle is is dynamicdynamic and and involves involves a anumber number of of regulators. regulators. STAG2 STAG2 mutation mutationss are are the the most most frequent, frequent, and inhibition of STAG1 subunitsubunit is is syntheticallysynthetically lethallethal with with STAG2 STAG2 mutations. mutations. Listed Listed are are the the cohesin cohesin regulators regulators that that can can be be pharmacologically pharmacologically inhibited inhibited and andtheir their inhibition inhibition mainly mainly disrupts disrupts cell cell cycle cycle progression. progression. (B) ( CohesinB) Cohesin subunit subunit SMC3 SMC3 acetylation acetylation during during S phase S phase ensures ensures sister sisterchromatid chromatid cohesion. cohesion. InIn most most vertebrates, vertebrates, the the two two mitotic mitotic complexes complexes cohesin–STAG1 cohesin–STAG1 and and cohesin–STAG2 cohesin–STAG2 areare required required to to maintain maintain sister sister chromatid chromatid co cohesionhesion at attelomeres telomeres and and centromeres, centromeres, respec- respec- tivelytively [27,28]. [27,28 STAG]. STAG proteins proteins form form a crucial a crucial interface interface for the for interaction the interaction of regulatory of regulatory sub- unitssubunits and cofactors. and cofactors. Additional Additional regulators regulators that associate that associate with the with core the cohesin core cohesin complex com- haveplex also have been also identified. been identified. BRCA2 BRCA2modulates modulates sister chromatid sister chromatid cohesion cohesion by limiting by limitingPDS5- mediatedPDS5-mediated STAG association STAG association and regulates and regulates cohesin cohesin binding binding at DNA at DNAreplication replication origins ori- [29,30].gins [29 PDL1,30]. can PDL1 substitute can substitute for Sororin for Sororin function function in a context-dependent in a context-dependent manner manner [31]. [31]. 3. Cohesin Function 3. Cohesin Function Cohesin is involved in a broad range of cellular functions. During mitosis, cohesin has Cohesin is involved in a broad range of cellular functions. During mitosis, cohesin roles in kinetochore bi-orientation [32], spindle assembly [33] and mitotic book-marking of has roles in kinetochore bi-orientation [32], spindle assembly [33] and mitotic book-mark- transcription factors [34]. However, only a fraction (~13%) of cohesin is involved in these ing of transcription factors [34]. However, only a fraction (~13%) of cohesin is involved in cell cycle functions. Most cellular cohesin functions in interphase [35]. these cell cycle functions. Most cellular cohesin functions in interphase [35]. In interphase, cohesin entraps DNA and, using its ATPase activity, extrudes DNA In interphase, cohesin entraps DNA and, using its ATPase activity, extrudes DNA to to form loops that are restricted by chromatin-bound CTCF (Figure2)[ 3,36–38]. Cohesin- form loops that are restricted by chromatin-bound CTCF (Figure 2) [3,36–38]. Cohesin- mediated DNA loops facilitate gene enhancer–promoter communication or form insulated mediated DNA loops facilitate gene enhancer–promoter communication or form insu- hubs that prevent ectopic transcription [39–41]. Cohesin along with CTCF is crucial for hier- latedarchal hubs organization that prevent of DNAectopic loops transcription into topologically [39–41]. associatedCohesin along domains with(TADs) CTCF is [40 crucial,42–44 ]. forTADs hierarchal are further organization segregated of DNA into compartmentsloops into topologically or can even associated be part ofdomains larger compart-(TADs) [40,42–44].ments, representing TADs are further active or segregated inactive chromatin into compartments [7,37,40,41 ,45or ,can46]. even The function be part of cohesinlarger compartments,regulatory proteins, representing NIPBL, active WAPL or andinactive PDS5, chromatin is also crucial [7,37,40,41,45,46]. for accurate loopThe function extrusion ofand cohesin chromatin regulatory organization proteins, [7 NIPBL,,8,46,47 ].WAPL RAD21 and and PDS5, NIPBL is depletionalso crucial strengthens for accurate compart- loop extrusionmentalization, and chromatin which led organi to thezation view [7,8,46,47]. that cohesin RAD21 mediated and NIPBL loop extrusion depletion counteracts strength- ensepigenetic compartmentalization, compartmentalization which led [40 ,41to ,46the]. vi Itew has that been cohesin suggested mediated that such loop counteraction extrusion counteractsmay be required epigenetic to prevent compartmentalization the largescale spread [40,41,46]. of transcriptionally It has been suggested active orthat inactive such counteractionstates [40,41, 46may]. Cohesin be required also to interacts prevent with the Polycomblargescale groupspread (PcG)
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