Figure 5.

Cartoon illustrating different pathways of viral interference with telomere maintenance during EBV-induced B-cell immortalization. Latent membrane protein 1 (LMP1) promotes the activation of telomerase through several pathways that regulate the transcription and nuclear translocation of human telomerase reverse transcriptase (hTERT), whereas LMP2A inhibits telomerase activity by transcriptional repression of hTERT. Activating mutation in the promoter region of hTERT may contribute to the capacity of EBV to regulate the activity of telomerase. EBNA1 and LMP1 promote telomere dysfunction by inducing oxidative stress and downregulation of TRF2, respectively. Telomere dysfunction in the absence of telomerase activity activates ALT in which telomeres homeostasis is maintained by HR, which results in telomere length heterogeneity. The generation of few extremely short telomeres may, together with the occurrence of activating mutations, contribute to the activation of telomerase.