Emerging themes in cohesin cancer biology

ABSTRACT Mutations of the cohesin complex in human cancer were first discovered ~10 years ago. Since then, researchers worldwide have demonstrated that cohesin is among the most commonly

mutated protein complexes in cancer. Inactivating mutations in genes encoding cohesin subunits are common in bladder cancers, paediatric sarcomas, leukaemias, brain tumours and other cancer

types. Also in those 10 years, the prevailing view of the functions of cohesin in cell biology has undergone a revolutionary transformation. Initially, the predominant view of cohesin was as

a ring that encircled and cohered replicated chromosomes until its cleavage triggered the metaphase-to-anaphase transition. As such, early studies focused on the role of tumour-derived

cohesin mutations in the fidelity of chromosome segregation and aneuploidy. However, over the past 5 years the cohesin field has shifted dramatically, and research now focuses on the primary

role of cohesin in generating, maintaining and regulating the intra-chromosomal DNA looping events that modulate 3D genome organization and gene expression. This Review focuses on recent

discoveries in the cohesin field that provide insight into the role of cohesin inactivation in cancer pathogenesis, and opportunities for exploiting these findings for the clinical benefit

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support SIMILAR CONTENT BEING VIEWED BY OTHERS EMERGING ROLES OF COHESIN-STAG2 IN CANCER Article 29 November 2024 COHESIN MUTATIONS IN ACUTE MYELOID LEUKEMIA Article 09 September 2024

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biology research in the T.W. laboratory is funded by NIH/National Cancer Institute (NCI) grant R01CA169345 and the Hyundai Hope on Wheels Foundation. The Lombardi Comprehensive Cancer Center

is funded by NIH/NCI Cancer Center Support Grant P30CA051008. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown

University School of Medicine, Washington, DC, USA Todd Waldman Authors * Todd Waldman View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to Todd Waldman. ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing interests. ADDITIONAL INFORMATION PEER REVIEW INFORMATION _Nature Reviews

Cancer_ thanks F. X. Real, A. Viny and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. PUBLISHER’S NOTE Springer Nature remains neutral with regard

to jurisdictional claims in published maps and institutional affiliations. GLOSSARY * Chromosomal instability The condition when cells have an abnormally high rate of mis-segregation of

replicated chromosomes to daughter cells in mitosis. Results in aneuploidy. * Aneuploidy The presence of an abnormal number of chromosomes in a cell, generally due to aberrant segregation of

replicated chromosomes to daughter cells in mitosis. * Chromatin immunoprecipitation-sequencing A technique that combines chromatin immunoprecipitation (ChIP) with next-generation DNA

sequencing to comprehensively identify, in an unbiased way, all of the genomic binding sites of chromatin-associated proteins. Often referred to as ChIP-seq. * Haematopoietic stem and

progenitor cells (HSPCs). Multipotent, self-renewing adult stem cells that give rise to all types of differentiated blood cells in the lymphoid and myeloid lineages. HSPCs are found

primarily in the bone marrow of adults, but are also found in umbilical cord blood and in peripheral blood. * Auxin-inducible degron A 68-amino-acid tag that, when added to an endogenous

protein via gene editing, makes it possible to rapidly and completely degrade the tagged protein by adding auxin to the culture medium. * Hi-C (High-throughput chromosome conformation

capture). A next-generation DNA sequencing-based technique that makes it possible to comprehensively identify, in an unbiased way, regions of the genome that tend to co-localize in the 3D

space comprising the interior of the nucleus. * 3D genome organization The 3D structure of chromosomes and their relative positioning in the nucleus. Sometimes also referred to as nuclear

organization. * Haploinsufficiency One of the two alleles of a gene is inactivated by mutation, resulting in a pathology such as cancer. Generally used to refer to tumour suppressor genes in

which inactivation of one allele produces cancer, whereas inactivation of both alleles is lethal to the cell. * Biomarkers Measurable biological substances, such as DNA, RNA or protein,

that provide predictive information about a patient’s likely clinical outcome. * Synthetic lethality The simultaneous inactivation of two gene products results in cell death, whereas

inactivation of only one of the gene products does not. When applied to anticancer drug discovery, one of the inactivated proteins is encoded by a mutated tumour suppressor gene and the

other protein is inactivated via pharmacological inhibition. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Waldman, T. Emerging themes in cohesin

cancer biology. _Nat Rev Cancer_ 20, 504–515 (2020). https://doi.org/10.1038/s41568-020-0270-1 Download citation * Accepted: 29 April 2020 * Published: 08 June 2020 * Issue Date: September

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