The Epstein–Barr virus nuclear antigen-1 promotes telomere dysfunction via induction of oxidative stress

The Epstein–Barr virus (EBV) nuclear antigen (EBNA)-1 promotes the accumulation of chromosomal aberrations in malignant B cells by inducing oxidative stress. Here we report that this phenotype is associated with telomere dysfunction. Stable or conditional expression of EBNA1 induced telomere abnormalities including loss or gain of telomere signals, telomere fusion and heterogeneous length of telomeres. This was accompanied by the accumulation of extrachromosomal telomeres, telomere dysfunction-induced foci (TIFs) containing phosphorylated histone H2AX and the DNA damage response protein 53BP1, telomere-associated promyelocytic leukemia nuclear bodies (APBs), telomeric-sister chromatid exchanges and displacement of the shelterin protein TRF2. The induction of TIFs and APBs was inhibited by treatment with scavengers of reactive oxygen species (ROS) that also promoted the relocalization of TRF2 at telomeres. These findings highlight a novel mechanism by which EBNA1 may promote malignant transformation and tumor progression

Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. similar to 85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining similar to 15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi's sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours. similar to 15% of cancers induce alternative lengthening of telomeres (ALT) to activate telomere maintenance. Here, the authors reveal that infection with Kaposi's sarcoma herpesvirus (KSHV) induces acquisition of ALT-like features in previously non-ALT cell lines.Peer reviewe

Gene dosage reductions of Trf1 and/or Tin2 induce telomere DNA damage and lymphoma formation in aging mice

Telomeres are essential structures that cap the end of chromosomes, which is required for maintenance of chromosomal stability, cell viability and the capacity of cells to proliferate. A complex of specific telomere-binding proteins (TRF1, TRF2, POT1, TIN2, TPP1 and RAP1), also known as the Shelterin complex, is essential for telomere capping by assisting the formation of tertiary telomeric structures.1 Gene mutations in components of the Shelterin complex (hTIN2, hPOT1 and hTPP1) lead to bone marrow failure and cancer formation in human genetic diseases including dyskeratosis congenita (DC), which is caused by Tin2 mutation in 20% of the cases.2, 3 All known TIN2 mutations are heterozygous, autosomal-dominant and patients normally show extremely short telomeres. In addition, mutations in the telomere binding protein POT1 were shown to lead to lymphocytic leukaemia formation.4 Aside from genetic diseases, a variety of studies reported reduced expression of telomere-binding proteins in human cancers compared with non-cancerous tissue suggesting that downregulation of the expression of telomere-binding proteins may also contribute to carcinogenesis in somatic cells and tissues.5, 6 It was shown that Epstein–Barr virus-encoded LMP1 and Epstein–Barr virus-infection itself induce the downregulation of TRF1, TRF2 and POT1 at the transcriptional and translational level resulting in complex chromosomal aberrations, alternative lengthening of telomeres and the induction of Hodgkin's lymphoma.7,