Merotelic attachments and non-homologous end joining are the basis of chromosomal instability
© Guerrero et al; licensee BioMed Central Ltd. 2010
Received: 18 April 2010
Accepted: 17 May 2010
Published: 17 May 2010
Although the large majority of solid tumors show a combination of mitotic spindle defects and chromosomal instability, little is known about the mechanisms that govern the initial steps in tumorigenesis. The recent report of spindle-induced DNA damage provides evidence for a single mechanism responsible for the most prominent genetic defects in chromosomal instability. Spindle-induced DNA damage is brought about by uncorrected merotelic attachments, which cause kinetochore distortion, chromosome breakage at the centromere, and possible activation of DNA damage repair pathways. Although merotelic attachments are common early in mitosis, some escape detection by the kinetochore pathway. As a consequence, a proportion of merotelic attachments gives rise to chromosome breakage in normal cells and in carcinomas. An intrinsic chromosome segregation defect might thus form the basis of tumor initiation. We propose a hypothesis in which merotelic attachments and chromosome breakage establish a feedback loop that results in relaxation of the spindle checkpoint and suppression of anti-proliferative pathways, thereby promoting carcinogenesis.
In addition to correct amphitelic attachment, several errors can occur in microtubule/kinetochore coupling (Fig. 1b, c, d). Individual kinetochores might not attach (monotelic attachment), and are left behind once chromosome segregation is initiated at anaphase. Kinetochores of both sister chromatids might attach to microtubules from a single spindle pole (syntelic attachment), and run the risk of segregation into the wrong daughter cell. A single kinetochore might capture microtubules from both spindle poles (merotelic attachment), which places physical stress on the centromere as the microtubules start to pull. The first two errors result in loss of spindle tension, are sensed as a lack of kinetochore stretch, and trigger a strong signal for mitotic checkpoint activation . Merotelic attachments generate kinetochore tension, however, and do not always activate the spindle checkpoint [8–10]. Although merotelic attachments are potentially harmful, they are relatively common in dividing cells, but are normally corrected early in mitosis [11, 12]. The control of the mitotic spindle however is deregulated in most carcinomas, resulting in a self-amplifying loop of chromosomal instability. Recent advances underline the importance of spindle defects in the early stages of tumorigenesis, and generate a particular interest in the role of spindle-induced chromosome breakage as the initiator of chromosomal instability . The aim of this paper is to discuss some of the signaling pathways that connect spindle defects, specifically merotelic attachments, to chromosome breakage and the regulation of cell cycle progression.
Coping with merotelic attachments
Uncorrected merotelic attachments lead to gains and losses of whole chromosomes, termed aneuploidy . In addition, uncorrected merotelic attachments can exert sufficient force to distort individual kinetochores, which damages centromeric chromatin and causes chromosome rupture . The alterations that result from uncorrected merotelic attachments (aneuploidy as well as losses and gains of chromosome arms) are among the most frequently observed genomic defects in cancer [14, 15]. Since uncorrected merotelic attachments appear to be common in solid tumors, thery are thought to be a driving force behind the chromosomal instability (CIN) phenotype that accounts for approximately 85% of sporadic carcinomas [16, 17]. The chromosome breakage that is associated with uncorrected merotelic attachments generates "reactive" chromosome arms that are able to fuse to intact chromosomes . Such "reactive" arms could initiate the self-propagating chain of instability termed the breakage-fusion-bridge cycle . Whereas the DNA breakage products of uncorrected merotelic attachments, whole chromosome arms, are especially common in low-grade tumors, complex translocation patterns are characteristic of high-grade carcinomas [19, 20]. In CIN tumors, uncorrected merotelic attachments might thus initiate genomic instability that is subsequently propagated by breakage-fusion-bridge cycles . Although uncorrected merotelic attachments are common in CIN tumors that show reduced spindle checkpoint control, some healthy cells also bear spindle defects. Genetic techniques using fluorescent probes that flank the centromere showed that a small proportion of normal lymphocytes undergo physical separation of the long and short arms of a single chromosome , indicating that some merotelic attachments lead inevitably to chromosome breakage. The uncorrected merotelic attachments responsible for the most important genomic alterations of CIN tumors thus occur occasionally in normal cells.
The prevalence of CIN in cancer and the evidence of uncorrected merotelic attachments in normal cells suggest that correct chromosome segregation is a fundamental problem in evolution, still not fully resolved. Some species, for example Muntiacus muntjak, Potorous tridactylis, and Wallabia bicolor [22–24], assemble their genome in a dozen or fewer chromosomes, with a concomitant reduction in centrosome number. Although low chromosome numbers reduce the number of kinetochores that require control in each cell division, individual kinetochores still form merotelic attachments in Potorous tridactylis cells . An extremely low chromosome number nonetheless appears to prevent aneuploidy, thought to be one of the initiating events in tumorigenesis [16, 26]. Conditions that readily induce aneuploidy in human and mouse cells only allow for loss or gain of the small sex chromosome Y2 in muntjac cells. Missegregation of the large chromosomes in muntjac is not tolerated due to gene dosage effects . Most mammals must live with the occasional aneuploid cell, however, because they fully depend on spindle dynamics to detect and prevent chromosome missegregation [12, 25].
How cells handle chromosome breaks in mitosis
Although merotelic attachments are processed by various pathways, a small proportion escapes detection , leaving the daughter cells to deal with a fragmented chromosome. Relaxation of the spindle checkpoint exacerbates this problem , placing additional pressure on DNA break repair in CIN tumors. In mammalian cells, double-strand breaks are repaired by two major processes, termed non-homologous end joining and homologous recombination . The availability of repair pathways at the time and subcellular location of intra-mitotic DSB has important consequences; whereas non-homologous end joining repairs breaks by simple religation of two DNA ends, homologous recombination depends on a homologous DNA template. This means that non-homologous end joining can repair DSB throughout the cell cycle, but homologous recombination is virtually inactive in the G1 phase . The DNA breaks caused by uncorrected merotelic attachments are physically the same as other DSB and their centromeric location does not in itself hinder efficient repair , but the cell cycle stage in which they are formed obliges the cell to correct DNA damage during or right after mitosis. In addition, some chromosome fragments are sequestered in micronuclei , resulting in physical separation from the remainder of chromosomes and precluding homologous recombination.
Mice deficient in any of the DSB repair proteins are generally hypersensitive to induced DNA damage, although they are usually viable [37, 38]. Whereas non-homologous end joining or homologous recombination repair mutants have problems repairing induced DSB, the inactivation of a single repair pathway does not result in spontaneous DSB accumulation [13, 39, 40]. The absence of spontaneous DNA damage in mice lacking a single repair pathway implies that the endogenous DSB formation rate must be relatively low or at least is not life threatening. Notwithstanding the low frequency of spontaneous DSB, many tumors show increased repair system activity, in particular that of non-homologous end joining [41–43]. Non-homologous end joining activation in cancer indicates that DSB are generated at an increased rate, possibly due to chromosome segregation errors and concomitant chromosome arm breakage.
Non-homologous end joining is essential in a CIN background
Combined disruption of Dido and Ku80 is embryonic lethal.
N° pups (expected)
N° pups (observed)
Combined disruption of Dido and DNA-PKcs.
N° pups (expected)
N° pups (observed)
Any minor alteration in spindle regulation could result in an increase in merotelic attachments that escape detection, giving rise to aneuploidy and chromosome breakage . Breakage activates cellular DNA damage control, shown by increased DSB repair in many tumors [41–43]. The need for non-homologous end joining in a CIN background is emphasized by the synthetic lethality of Dido Ku80 double mutants. DNA damage signaling provides feedback to the spindle checkpoint and delays mitosis progression, which prolongs the time window for repair and prevents aneuploidy. Repair by non-homologous end joining not only limits DNA damage and promotes cell survival, but also catalyzes the fusion of reactive chromosome ends. A chromosome fragment generated by spindle defects can thus form end-to-end fusions with normal chromosomes and initiate the breakage-fusion-bridge cycle . Once the breakage-fusion-bridge cycles commence, restoring spindle control no longer ensures stability, since dicentric chromosomes formed by end-to-end fusions can break, even though individual kinetochores are correctly attached [17, 18]. A long term effect of DNA damage is cell immortalization; sustained breaks exert selective pressure to evade apoptosis and senescence . Since DSB prevent the progression of mitosis, it is likely that sustained breaks also facilitate mitotic checkpoint relaxation. Continuous mitotic chromosome breakage could thus explain why, over time, CIN tumors become more malignant and refractory to treatment. In conclusion, nature's use of DSB repair systems as a backup for the detection of merotelic attachments might in fact promote chromosomal instability and act as a motor for carcinogenesis. CIN tumors show precisely the characteristics predicted by the above model: Most carcinomas show chromosomal instability and reduced control of the mitotic spindle, combined with enhanced DNA damage repair and reduced apoptotic potential. The challenge for cancer treatment will be to break this vicious circle without causing additional genomic instability.
double strand DNA break.
The authors thank Dr. Maria Blasco for Ku80 and DNA-PKcs mutant mice, and Catherine Mark for editorial assistance. The publication costs for this manuscript were financed by grant PS09/00572 (Fondo de Investigación en Salud) and the experimental work by grant S-BIO-0189-2006 (Comunidad Autonoma de Madrid). The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (CSIC) and by Pfizer.
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