{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:09:20Z","timestamp":1791295760421,"version":"4.1.0"},"reference-count":37,"publisher":"The Company of Biologists","issue":"24","license":[{"start":{"date-parts":[[2000,12,15]],"date-time":"2000-12-15T00:00:00Z","timestamp":976838400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,12,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Telomere maintenance is essential for the unlimited proliferative potential of human cells, and hence immortalization. However, a number of tumors, tumorderived cell lines and in vitro immortalized cell lines have been described that do not express detectable telomerase activity. These lines utilize a mechanism, termed Alternative Lengthening of Telomeres (ALT), to provide telomere maintenance. A subset of the cells in each ALT cell line contain a novel form of the promyelocytic leukemia nuclear body (PML NB) in which telomeric DNA and the telomere binding proteins TRF1 and TRF2 co-localize with the PML protein, termed ALT-associated PML bodies (AA-PBs). In contrast, in non-ALT, telomerase-positive cell lines these telomeric proteins and the PML NB occupy distinct and separate subnuclear domains. PML NBs have been implicated in terminal differentiation, growth suppression and apoptosis. The role, if any, of AA-PBs in telomere maintenance or culture viability in telomerase negative cell lines is unclear, but it has been suggested that cells containing these structures are no longer viable and are marked for eventual death. We utilized a series of human ovarian surface epithelium (HOSE) cell lines that use ALT for telomere maintenance to determine if AA-PBs are indeed markers of cells in these cultures that are no longer cycling. We show that AA-PB positive cells incorporate BrdU and thus are able to carry out DNA replication. In addition, AA-PBs are present in mitotic cells and the frequency of cells containing these structures is increased when cultures are enriched for cells in the G2\/M phase of the cell cycle suggesting that the formation of AA-PBs is coordinately regulated with the cell cycle. Finally, we demonstrate that the majority of the AA-PB positive cells in the culture are not destined for immediate apoptosis. Taken together the data argue against AA-PBs marking cells destined for death and, instead, raise the possibility that these structures may be actively involved in telomere maintenance via the ALT pathway.<\/jats:p>","DOI":"10.1242\/jcs.113.24.4577","type":"journal-article","created":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T18:31:24Z","timestamp":1619375484000},"page":"4577-4585","source":"Crossref","is-referenced-by-count":141,"title":["ALT-associated PML bodies are present in viable cells and are enriched in cells in the G2\/M phase of the cell cycle"],"prefix":"10.1242","volume":"113","author":[{"given":"Jennifer V.","family":"Grobelny","sequence":"first","affiliation":[{"name":"Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia PA, 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew K.","family":"Godwin","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia PA, 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Broccoli","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia PA, 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2000,12,15]]},"reference":[{"key":"2023101823044469400_JOCES_113_24_4577C1","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/0002-9378(95)90282-1","article-title":"Expression of two mucin antigens in cultured human ovarian surface epithelium: influence of a family history of ovarian cancer","volume":"173","author":"Auersperg","year":"1995","journal-title":"Am. J. Obstet. Gynec"},{"key":"2023101823044469400_JOCES_113_24_4577C2","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1126\/science.279.5349.349","article-title":"Extension of life-span by introduction of telomerase into normal human cells","volume":"279","author":"Bodnar","year":"1998","journal-title":"Science"},{"key":"2023101823044469400_JOCES_113_24_4577C3","doi-asserted-by":"publisher","first-page":"9082","DOI":"10.1073\/pnas.92.20.9082","article-title":"Telomerase activity in normal and malignant hematopoietic cells","volume":"92","author":"Broccoli","year":"1995","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"2023101823044469400_JOCES_113_24_4577C4","doi-asserted-by":"publisher","first-page":"3765","DOI":"10.1128\/MCB.16.7.3765","article-title":"Telomerase activation in mouse mammary tumors: lack of telomere shortening and evidence for regulation of telomerase with RNA cell proliferation","volume":"16","author":"Broccoli","year":"1996","journal-title":"Mol. Cell Biol"},{"key":"2023101823044469400_JOCES_113_24_4577C5","doi-asserted-by":"publisher","first-page":"4240","DOI":"10.1002\/j.1460-2075.1995.tb00098.x","article-title":"Telomere elongation in immortal human cells without detectable telomerase activity","volume":"14","author":"Bryan","year":"1995","journal-title":"EMBO J"},{"key":"2023101823044469400_JOCES_113_24_4577C6","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1038\/nm1197-1271","article-title":"Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines [see comments]","volume":"3","author":"Bryan","year":"1997","journal-title":"Nature Med"},{"key":"2023101823044469400_JOCES_113_24_4577C7","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1182\/blood.V88.3.1052.1052","article-title":"In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha\/PML proteins","volume":"88","author":"Chen","year":"1996","journal-title":"Blood"},{"key":"2023101823044469400_JOCES_113_24_4577C8","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1126\/science.270.5242.1663","article-title":"A human telomeric protein","volume":"270","author":"Chong","year":"1995","journal-title":"Science"},{"key":"2023101823044469400_JOCES_113_24_4577C9","doi-asserted-by":"publisher","first-page":"14723","DOI":"10.1073\/pnas.95.25.14723","article-title":"Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization","volume":"95","author":"Counter","year":"1998","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"2023101823044469400_JOCES_113_24_4577C10","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/0092-8674(94)90340-9","article-title":"A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein","volume":"76","author":"Dyck","year":"1994","journal-title":"Cell"},{"key":"2023101823044469400_JOCES_113_24_4577C11","doi-asserted-by":"publisher","first-page":"4581","DOI":"10.1242\/jcs.112.24.4581","article-title":"Cell cycle regulation of PML modification and ND10 composition","volume":"112","author":"Everett","year":"1999","journal-title":"J. Cell Sci"},{"key":"2023101823044469400_JOCES_113_24_4577C12","doi-asserted-by":"publisher","first-page":"2905","DOI":"10.1038\/sj.onc.1201811","article-title":"Cooperation between the RING+B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival","volume":"16","author":"Fagioli","year":"1998","journal-title":"Oncogene"},{"key":"2023101823044469400_JOCES_113_24_4577C13","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1038\/13495","article-title":"Inhibition of telomerase limits the growth of human cancer cells","volume":"5","author":"Hahn","year":"1999","journal-title":"Nature Med"},{"key":"2023101823044469400_JOCES_113_24_4577C14","doi-asserted-by":"publisher","first-page":"14276","DOI":"10.1073\/pnas.96.25.14276","article-title":"Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death","volume":"96","author":"Herbert","year":"1999","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"2023101823044469400_JOCES_113_24_4577C15","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1182\/blood.V72.2.567.567","article-title":"Use of all-trans retionoic acid in the treatment of acute promyelocytic leukemia","volume":"72","author":"Huang","year":"1988","journal-title":"Blood"},{"key":"2023101823044469400_JOCES_113_24_4577C16","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1083\/jcb.147.2.221","article-title":"PML is critical for ND10 formation and recruits the PML-interacting proten Daxx to this nuclear structure when modified by SUMO-1","volume":"147","author":"Ishov","year":"1999","journal-title":"J. Cell Biol"},{"key":"2023101823044469400_JOCES_113_24_4577C17","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific association of human telomerase activity with immortal cells and cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"2023101823044469400_JOCES_113_24_4577C18","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1093\/genetics\/152.1.143","article-title":"RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase","volume":"152","author":"Le","year":"1999","journal-title":"Genetics"},{"key":"2023101823044469400_JOCES_113_24_4577C19","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1128\/MCB.20.5.1784-1796.2000","article-title":"Sequestration and inhibition of Daxx-mediated transcriptional repression by PML","volume":"20","author":"Li","year":"2000","journal-title":"Mol. Cell Biol"},{"key":"2023101823044469400_JOCES_113_24_4577C20","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1083\/jcb.135.4.867","article-title":"Structure, subnuclear distribution, and nuclear matrix association of the mammalian telomeric complex","volume":"135","author":"Lud\u00e9rus","year":"1996","journal-title":"J. Cell Biol"},{"key":"2023101823044469400_JOCES_113_24_4577C21","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/0092-8674(93)90234-H","article-title":"An alternative pathway for yeast telomere maintenance rescues est1-senescence","volume":"73","author":"Lundblad","year":"1993","journal-title":"Cell"},{"key":"2023101823044469400_JOCES_113_24_4577C22","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1093\/emboj\/17.1.61","article-title":"Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus","volume":"17","author":"Muller","year":"1998","journal-title":"EMBO J"},{"key":"2023101823044469400_JOCES_113_24_4577C23","doi-asserted-by":"crossref","DOI":"10.1007\/BF00981880","article-title":"Detection of telomerase activity in human cells and tumors by a telomeric repeat amplification protocol (TRAP)","volume-title":"Meth. Cell Sci","author":"Piatyszek","year":"1995"},{"key":"2023101823044469400_JOCES_113_24_4577C24","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/3068","article-title":"PML induces a novel caspase-independent death process","volume":"20","author":"Quignon","year":"1998","journal-title":"Nature Genet"},{"key":"2023101823044469400_JOCES_113_24_4577C25","first-page":"1254","article-title":"Immortalized cells with no detectable telomerase activity. A review","volume":"62","author":"Reddel","year":"1997","journal-title":"Biochemistry (Moscow)"},{"key":"2023101823044469400_JOCES_113_24_4577C26","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/S0959-8049(97)00062-2","article-title":"A survey of telomerase activity in human cancer","volume":"33","author":"Shay","year":"1997","journal-title":"Eur. J. Cancer"},{"key":"2023101823044469400_JOCES_113_24_4577C27","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/S0171-2985(97)80051-4","article-title":"Nuclear dots: Actors on many stages","volume":"198","author":"Sternsdorf","year":"1997","journal-title":"Immunobiology"},{"key":"2023101823044469400_JOCES_113_24_4577C28","doi-asserted-by":"publisher","first-page":"6037","DOI":"10.1093\/emboj\/18.21.6037","article-title":"Human Daxx regulates Fas-induced apoptosis form nuclear PML oncogenic domains (PDOs)","volume":"18","author":"Torii","year":"1999","journal-title":"EMBO J"},{"key":"2023101823044469400_JOCES_113_24_4577C29","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1038\/385740a0","article-title":"Control of telomere length by the human telomeric protein TRF1","volume":"385","author":"van Steensel","year":"1997","journal-title":"Nature"},{"key":"2023101823044469400_JOCES_113_24_4577C30","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/S0960-9822(98)70109-5","article-title":"Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span","volume":"8","author":"Vaziri","year":"1998","journal-title":"Curr. Biol"},{"key":"2023101823044469400_JOCES_113_24_4577C31","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/3073","article-title":"PML is essential for multiple apoptotic pathways","volume":"20","author":"Wang","year":"1998","journal-title":"Nature Genet"},{"key":"2023101823044469400_JOCES_113_24_4577C32","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1126\/science.279.5356.1547","article-title":"Role of PML in cell growth and the retinoic acid pathway","volume":"279","author":"Wang","year":"1998","journal-title":"Science"},{"key":"2023101823044469400_JOCES_113_24_4577C33","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/0092-8674(94)90341-7","article-title":"Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells","volume":"76","author":"Weiss","year":"1994","journal-title":"Cell"},{"key":"2023101823044469400_JOCES_113_24_4577C34","first-page":"971","article-title":"Involvement of RB-1, p53, p16INK4 and telomerase in immortalisation of human cells","volume":"11","author":"Whitaker","year":"1995","journal-title":"Oncogene"},{"key":"2023101823044469400_JOCES_113_24_4577C35","article-title":"NBS1 and TRF1 colocalize at PML bodies during late S\/G2 phases in immortalized telomerase-negative cells: Implications of NBS1 in alternative lengthening of telomeres","volume-title":"J. Biol. Chem","author":"Wu","year":"2000"},{"key":"2023101823044469400_JOCES_113_24_4577C36","first-page":"4175","article-title":"Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body","volume":"59","author":"Yeager","year":"1999","journal-title":"Cancer Res"},{"key":"2023101823044469400_JOCES_113_24_4577C37","doi-asserted-by":"publisher","first-page":"2388","DOI":"10.1101\/gad.13.18.2388","article-title":"Telomere shortening and apoptosis in telomerase-inhibited human tumor cells","volume":"13","author":"Zhang","year":"1999","journal-title":"Genes Dev"}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/113\/24\/4577\/3237519\/joces_113_24_4577.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/113\/24\/4577\/3237519\/joces_113_24_4577.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T23:07:53Z","timestamp":1697670473000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/113\/24\/4577\/26389\/ALT-associated-PML-bodies-are-present-in-viable"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,12,15]]},"references-count":37,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2000,12,15]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.113.24.4577","relation":{},"ISSN":["0021-9533","1477-9137"],"issn-type":[{"value":"0021-9533","type":"print"},{"value":"1477-9137","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,12,15]]}}}