Telomere dysfunction and activation of alternative lengthening of telomeres in B-lymphocytes infected by Epstein-Barr virus

Oncogene. 2013 Dec 5;32(49):5522-30. doi: 10.1038/onc.2013.189. Epub 2013 May 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / virology*
  • DNA Helicases / metabolism
  • Enzyme Activation
  • Epstein-Barr Virus Infections / genetics*
  • Herpesvirus 4, Human*
  • Humans
  • Nuclear Proteins / metabolism
  • Sister Chromatid Exchange
  • Telomerase / metabolism
  • Telomere / genetics*
  • Telomere Homeostasis / genetics*
  • Telomere-Binding Proteins / metabolism
  • Telomeric Repeat Binding Protein 1 / metabolism
  • Telomeric Repeat Binding Protein 2 / metabolism
  • X-linked Nuclear Protein

Substances

  • Nuclear Proteins
  • POT1 protein, human
  • TERF2 protein, human
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 1
  • Telomeric Repeat Binding Protein 2
  • Telomerase
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein