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The Impact of Mitotic Errors on Cell Proliferation and Tumorigenesis

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The Impact of Mitotic Errors on Cell Proliferation and Tumorigenesis Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The impact of mitotic errors on cell proliferation and tumorigenesis Michelle S. Levine and Andrew J. Holland Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA Mitosis is a delicate event that must be executed with In this review, we discuss possible sources of mitotic er- high fidelity to ensure genomic stability. Recent work rors and the effect of these mistakes on cell physiology has provided insight into how mitotic errors shape cancer and tumorigenesis. We then describe recent findings sug- genomes by driving both numerical and structural alter- gesting that errors in cell division are recognized by the ations in chromosomes that contribute to tumor initia- immune system and that tumor cells with complex karyo- tion and progression. Here, we review the sources of types may evolve mechanisms to counteract this recogni- mitotic errors in human tumors and their effect on cell fit- tion. We conclude with a discussion of how mistakes in ness and transformation. We discuss new findings that cell division or their associated consequences can be tar- suggest that chromosome missegregation can produce a geted therapeutically to benefit patients with cancer. proinflammatory environment and impact tumor respon- siveness to immunotherapy. Finally, we survey the vul- nerabilities exposed by cell division errors and how they Sources of mitotic errors can be exploited therapeutically. Cancer genomes are fluid, shape-shifting entities owing to a variety of genetic instability phenotypes, each of which exhibits its own unique mutational signature. Chromo- somal instability (CIN) refers to the ongoing acquisition of genomic alterations that involve high rates of chromo- To err is human some gain and loss (Lengauer et al. 1997). CIN is recog- Each day, millions of cells in our bodies undergo division nized as a general property of most aneuploid cancer cell to support growth and replace lost or damaged cells in lines and drives intratumoral heterogeneity, which allows our tissues. Numerous safeguards have evolved to ensure for adaptation to changing environmental conditions (van that these divisions proceed only under ideal growth con- Jaarsveld and Kops 2016). It is important to recognize that ditions and with high fidelity. Mistakes during mitosis CIN and aneuploidy are distinct traits that are likely to lead to the production of daughter cells with too many have different impacts on tumor evolution and clinical or too few chromosomes, a feature known as aneuploidy. behavior. While aneuploidy is a genetic state, CIN refers Nearly all aneuploidies that arise due to mistakes in mei- to the rate at which karyotypes diverge. Therefore, while osis or during early embryonic development are lethal, CIN invariably leads to aneuploidy, cells can be stably an- with the notable exception of trisomy 21 in humans. euploid without exhibiting CIN. Below, we discuss the However, mitotic errors that give rise to aneuploidy later causes of CIN and how cell division errors contribute to in life have been linked to aging and tumorigenesis (Nay- the evolution of malignant karyotypes in human cancers. lor and van Deursen 2016). Aneuploidy is a very common feature of cancer, arising Spindle assembly checkpoint (SAC) defects in almost 70% of solid human tumors (Duijf et al. 2013). In addition to alterations in chromosome number, tumor The objective of mitosis is to faithfully segregate the repli- cells show frequent structural alterations in chromo- cated chromosomes into two new daughter cells. This is somes that include deletions, amplifications, and translo- achieved by the attachment of chromosomes to microtu- cations. Errors in mitosis are the major source of bules (MTs) of the mitotic spindle apparatus. Chromo- numerical changes in chromosome number observed in somes attach to ends of MTs at specialized protein cancer and also have been recognized recently to be a con- structures, known as kinetochores, that assemble onto tributing factor in the generation of chromosomal rear- centromeric chromatin. Replicated chromosomes have rangements (Bakhoum et al. 2014; Leibowitz et al. 2015). © 2018 Levine and Holland This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue [Keywords: aneuploidy; chromosomal instability; mitosis] publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding author: [email protected] After six months, it is available under a Creative Commons License (At- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.314351. tribution-NonCommercial 4.0 International), as described at http:// 118. creativecommons.org/licenses/by-nc/4.0/. 620 GENES & DEVELOPMENT 32:620–638 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/18; www.genesdev.org Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press The impact of mitotic errors in cancer two kinetochores, and biorientation is achieved when lowering APC/C activity can render the SAC nonessential each sister kinetochore binds MTs oriented toward oppo- in human colorectal cancer cells (Wild et al. 2016; Sansre- site spindle poles. A surveillance mechanism known as gret et al. 2017), and some cells lacking the SAC compo- the SAC delays the separation of the sister chromatids at nent MAD2 can proliferate in vitro and in vivo if p53 is anaphase until all of the kinetochores have made correct inactivated to allow tolerance to high levels of genome in- attachments to spindle MTs (Fig. 1A). Components of stability (Burds et al. 2005; Foijer et al. 2017). the SAC localize to unattached kinetochores and function The SAC is not an all-or-nothing response, but rather in a biochemical signaling cascade to inhibit activation of the strength of the signal depends on the number of unat- the CDC20-bound anaphase-promoting complex/cyclo- tached kinetochores (Collin et al. 2013). Thus, mutations some (APC/CCdc20), an E3 ubiquitin ligase that targets Cy- that weaken the SAC can result in precocious anaphase clin B and Securin for degradation by the proteasome (Fig. onset before complete kinetochore attachment, which 1A). Securin destruction liberates Separase, which then dramatically increases the probability of chromosome cleaves and inactivates the cohesin complex that holds missegregation. Mouse models have shown that attenuat- the sister chromatids together, thereby allowing sister ing the SAC promotes aneuploidy and genome instability chromatid separation and the onset of anaphase (Fig. 1B). in vivo (Simon et al. 2015). Moreover, mutations in the Degradation of Cyclin B inactivates cyclin-dependent ki- SAC proteins TRIP13 and BUBR1 cause mosaic variegated nase 1 (Cdk1), allowing mitotic exit and the completion aneuploidy (MVA), a rare disorder characterized by high of cell division. levels of aneuploidy and an increased incidence of tumor- In mammals, inactivation of the SAC leads to dramatic igenesis (Hanks et al. 2004; Suijkerbuijk et al. 2010; Yost chromosome segregation errors; thus, the SAC is essential et al. 2017). Nevertheless, mutations in SAC genes are for organismal development and the viability of most rare in human tumors, and cells with CIN do not generally mammalian cells. However, while most cells require the enter anaphase precociously, indicating that SAC dys- SAC for continued growth, examples have emerged where function is not a major contributor to the mitotic errors the requirement for the SAC can be bypassed. For exam- and karyotypic heterogeneity observed in human cancer ple, extending the time for chromosome alignment by cells (Holland and Cleveland 2012b). A The Spindle Assembly Checkpoint (SAC) Figure 1. Chromosome segregation and sources of mi- SAC ON SAC OFF totic errors. (A) Unattached kinetochores activate an in- Bi-orientation Monotelic Anaphase onset inhibited Cell proceeds to anaphase hibitory SAC signal, which in turn blocks progression to APC/C active anaphase. The target of the SAC is the APC/C, an E3 MAD2 APC/C CDC20 ubiquitin ligase that targets several proteins for degrada- BUB3 Inactive MAD1 MAD1 BUB1 BUB3 BUBR1 tion, including Cyclin B1 and Securin. When all kineto- BUBR1 CDC20 Ub OR BUB3 Ub MAD2 CENP-E Ub Securin Ub chores are correctly attached to MTs emerging from MPS1 Ub Securin Ub Cyclin B Separase opposite poles of the cell (biorientation), the SAC is CDK1 CDK1 silenced, and APC/CCDC20 ubiquitinates and targets for Cyclin B Separase Syntelic degradation Cyclin B (to inactivate CDK1 and allow for mitotic exit) and Securin (to liberate the protease B Cohesion cleavage for anaphase progression Separase and initiate the onset of anaphase). (B) Replicat- Chromosome Sister chromatids ed sister chromatids are held together by the cohesin complex of proteins. Following silencing of the SAC, Securin is degraded, and the protease Separase is activat- ed. Separase cleaves the cohesin complex to allow for sis- Separase Cohesin Metaphase Anaphase ter chromatid separation and anaphase onset. (C) Extra centrosomes can generate a transient multipolar spindle, Centrosome amplification 2N 2N Diploid C Lagging anaphase which, following centrosome clustering, leads to an in- Centrosome chromosome clustering Diploid creased rate of merotelic attachments, where one sister 2N 2N + Merotelic Micronucleus kinetochore is attached to
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