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 of patients with cohesin-mutant cancers.

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Fig. 1: Canonical model of cohesin action.
Fig. 2: Current models of the effects of STAG2 inactivation on individual chromatin loops.
Fig. 3: Functions of cohesin in haematopoietic stem cell self-renewal and differentiation.
Fig. 4: Translational potential of cohesin mutations in cancer.

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Acknowledgements

Cohesin cancer 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.

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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.

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Waldman, T. Emerging themes in cohesin cancer biology. Nat Rev Cancer 20, 504–515 (2020). https://doi.org/10.1038/s41568-020-0270-1

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