title: Telomere dysfunction and activation of alternative lengthening of telomeres in B-lymphocytes infected by Epstein-Barr virus.
abstract: Malignant cells achieve replicative immortality by two alternative mechanisms, a common one dependent on de novo synthesis of telomeric DNA by telomerase, and a rare one based on telomere recombination known as alternative lengthening of telomeres (ALT). Epstein-Barr virus (EBV) transforms human B-lymphocytes into lymphoblastoid cell lines with unlimited growth potential in vitro and in vivo. Here we show that newly EBV-infected cells exhibit multiple signs of telomere dysfunction, including the occurrence of extra-chromosomal telomeres, telomere fusion and telomere length heterogeneity, and undergo progressive increase in telomere length without a parallel increase in telomerase activity. This phenotype is accompanied by the accumulation of telomere-associated promyelocytic leukemia nuclear bodies and telomeric-sister chromatid exchange, suggesting that EBV infection promotes the activation of ALT. Newly infected cells also display a significant reduction of telomere-associated TRF2 and express low levels of TRF1, TRF2, POT1 and ATRX, pointing to telomere de-protection as an important correlate of ALT activation. Collectively, these findings highlight the involvement of recombination-dependent mechanisms for maintenance of telomere homeostasis in EBV-induced B-cell immortalization.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: S A
authors.initials: SA
authors.lastname: Kamranvar
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: M G
authors.initials: MG
authors.lastname: Masucci
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D004265:DNA Helicases / Q000378:metabolism; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000235:genetics*; D004854:Herpesvirus 4, Human; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D000089804:Shelterin Complex; D012854:Sister Chromatid Exchange; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; C440849:POT1 protein, human; D000089804:Shelterin Complex; C504753:TERF2 protein, human; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein