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Chromosomal Instability Is Correlated with Telomere Erosion And Oncogene (1998) 16, 1825 ± 1838 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human ®broblasts expressing human papillomavirus type 16 E6 oncoprotein Leonid Filatov, Vita Golubovskaya, John C Hurt, Laura L Byrd, Jonathan M Phillips and William K Kaufmann Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA Cell cycle checkpoints and tumor suppressor gene functions Introduction appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal Chromosomal instability is common in cancer cells destabilization was monitored in relation to telomere (Holliday, 1989; Hartwell and Kastan, 1994). Not only structure, lifespan control and G2 checkpoint function. do cancers display abnormalities of chromosomes, be Replicative senescence was inactivated in secondary they polyploidy, aneuploidy, interstitial deletions and cultures of human skin ®broblasts by expressing the human ampli®cations, or a single marker chromosome, but papillomavirus type 16 (HPV-16) E6 oncoprotein to malignant cells also appear to acquire such abnormal- inactivate p53. Chromosome aberrations were enumerated ities at increased rates in comparison to their normal during in vitro aging of isogenic control (F5neo) and HPV- progenitors. The mechanisms of genetic instability in 16E6-expressing (F5E6) ®broblasts. We found that cancer cells are, therefore, of considerable interest. structural and numerical aberrations in chromosomes were Chromosome instability in human cells may be caused signi®cantly increased in F5E6 cells during aging in vitro by defects in various elements of DNA metabolism and ¯uorescence in situ hybridization (FISH) analysis using including replication, chromosome segregration, repair chromosome-speci®c probes demonstrated the occurrence and recombination processes (Hartwell, 1992; Cohen of rearrangements involving chromosome 4 and 6 in and Levy 1989; Coquelle et al., 1997). Chromosomal genetically unstable F5E6 cells. Flow cytometry and aberrations and alterations in DNA ploidy can be karyotypic analyses revealed increased polyploidy and induced by treatments with various drugs that damage aneuploidy in F5E6 cells only at passages 416, although DNA, including chemotherapeutic agents and chemical these cells displayed defective mitotic spindle checkpoint carcinogens, or by exposure to ionizing and ultraviolet function associated with inactivation of p53 at passages 5 radiations. Remarkably, expression of viral oncopro- and 16. G2 checkpoint function was con®rmed to be teins that inactivate tumor suppressor gene functions gradually but progressively inactivated during in vitro aging also induces chromosomal aberrations (Stewart and of E6-expressing cells. Aging of F5neo ®broblasts was Bacchetti, 1991; Chang et al., 1997), implying that documented during in vitro passaging by induction of a chromosome stability is preserved by tumor suppressor senescence-associated marker, pH 6.0 lysosomal b-galac- gene expression. tosidase. F5E6 cells displayed extension of in vitro lifespan The tumor suppressor genes p53 and pRB serve and did not induce b-galactosidase at high passage. Erosion within checkpoint circuits that regulate cell division. of telomeres during in vitro aging of telomerase-negative Cell cycle checkpoints represent positions of control F5neo cells was demonstrated by Southern hybridization that ensure the completion of dependent events in the and by quantitative FISH analysis on an individual cell cell division cycle and provide more time for DNA level. Telomeric signals diminished continuously as F5neo repair before DNA replication and mitosis (Hartwell cells aged in vitro being reduced by 80% near the time of and Kastan, 1994). Two DNA damage-responsive replicative senescence. Telomeric signals detected by FISH checkpoints act to delay the G1?S and G2?M cycle also decreased continuously during aging of telomerase- phase transitions (Kaufmann and Paules, 1996). negative F5E6 cells, but telomeres appeared to be stabilized Inactivation of p53 ablates G1 checkpoint function at passage 34 when telomerase was expressed. Chromoso- and is associated with gene ampli®cation and mal instability in E6-expressing cells was correlated chromosomal instability in human ®broblasts (Yin et (P50.05) with both loss of telomeric signals and al., 1992; Livingstone et al., 1992; White et al., 1994). inactivation of G2 checkpoint function. The results suggest Ataxia telangiectasia cells that are defective in both G1 that chromosomal stability depends upon a complex and G2 checkpoint functions display enhanced interaction among the systems of telomere length main- frequencies of spontaneous and radiation-induced tenance and cell cycle checkpoints. chromosomal aberrations (Taylor et al., 1976; Zam- petti-Bosseler and Scott, 1981; Ejima and Sasaki, Keywords: chromosome; instability; telomere; cell cycle; 1986). Defects in G2 checkpoint function were checkpoint associated with enhanced frequencies of radiation- induced chromosome breaks in a panel of human cancer lines (Schwartz et al., 1996). Cell cycle Correspondence: WK Kaufmann checkpoints, consequently, appear to preserve genetic Received 14 August 1997; revised 4 November 1997; accepted 5 stability and suppress carcinogenesis (Hartwell, 1992; November 1997 Kaufmann and Kaufman, 1993). Chromosomal instability in HPV-16E6-expressing fibroblasts L Filatov et al 1826 The clastogenic eects of oncogenic viruses have telomeres may be sensed as irreparable DNA damage been related in part to their abilities to bind to and signals by the p53-dependent G1 checkpoint (Dulic et inactivate tumor-suppressor genes (Stewart and Bac- al., 1994; Kaufmann and Paules, 1996). Telomere chetti, 1991; Chang et al., 1997). Certain viruses, such length can be maintained in immortal cells, stem cells as SV40, adenovirus and oncogenic strains of human and germ-line cells by a ribonucleoprotein enzyme, papillomavirus (HPV), alter the functions of the telomerase, which adds new telomeric repeats to protein products of p53 and pRB. In the case of chromosome ends (for review see Greider and Black- HPV-16, the E6 gene product targets p53 for ubiquitin- burn, 1985; Kim et al., 1994). An alternative mediated proteolysis (Schener et al., 1990; Galloway mechanism for telomere maintenance in immortal et al., 1994). A strain of HPV with low oncogenicity human cell lines may involve recombination (Bryan et (HPV-6) expresses an E6 protein that is unable to al., 1995; Rogan et al., 1995). Recently a human target p53 for proteolysis and fails to inactivate the G1 telomeric-repeat binding factor TRF1 was shown to be checkpoint (Galloway et al., 1994). Carcinogenesis by involved in telomere length regulation (van Steensel HPV-16 therefore appears to depend upon inactivation and de Lange, 1997). It was proposed that the binding of p53 function by its E6 gene. HPV-16E6-immorta- of TRF1 controls telomere length in cis by inhibiting lized human urothelial cells displayed high frequencies the action of telomerase at the ends of individual of unstable chromosomal aberrations and stable telomeres (van Steensel and de Lange, 1997). marker chromosomes as an example of the chromoso- To explore further the mechanisms of chromosomal mal instability that develops in HPV-16E6-expressing instability in HPV-16E6-expressing cells that lack the cells (Rezniko et al, 1994). By using an amphotropic replicative senescence checkpoint function, we have retrovirus to induce synchronous expression of HPV- monitored cellular aging during in vitro proliferation 16E6 in neonatal human skin ®broblasts, it was by assay of senescence-associated b-galactosidase possible to monitor the kinetics of cell cycle expression and by quantitative analysis of telomere checkpoint inactivation and chromosomal destabiliza- structure. In an attempt to identify the origin of tion under the in¯uence of a viral oncoprotein. dierent chromosome aberrations we analysed chro- Expression of the HPV-16E6 oncoprotein in neonatal mosomal instability in relation to telomere structure human diploid ®broblasts inactivated the G1 check- and G2 checkpoint function. The development of point (Dulic et al., 1994), but the G2 checkpoint was chromosomal abnormalities was correlated (P50.05) unaected initially (Paules et al., 1995; Levedakou et with both telomere erosion and attenuation of G2 al., 1995) and cells were normal cytogenetically (White checkpoint function in HPV-16E6-expressing cells. et al., 1994). However, as E6-expressing cells aged in Chromosomal stability appears to depend upon a vitro they displayed increased frequencies of chromo- complex interaction among the systems of telomere somal abnormalities including telomere associations, length maintenance and cell cycle checkpoints. chromosomal aberrations and aneuploidy (White et al., 1994; Kaufmann et al., 1997). This chromosomal instability was associated with concurrent attenuation Results of G2 checkpoint function (Paules et al., 1995; Kaufmann et al., 1997). The results suggested that Age-dependent appearance of chromosomal instability in oncogene-mediated inactivation of p53 can lead to F5E6 ®broblasts subsequent genetic alterations during cellular aging that deregulate the G2 checkpoint and induce We used two human ®broblast
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