Fig. 2

Telomere structure and maintenance mechanisms. The basic structure of telomere DNA (a double-stranded telomere repeat region that terminates in a 3′ single-stranded overhang) and the major telomere protection complex (shelterin) are illustrated on the left and the two telomere maintenance mechanisms are shown on the right [46, 47, 63]. Shelterin comprises a network of six proteins that collectively bind to both the double-stranded telomere repeats and the 3’-overhangs. This special nucleoprotein complex stabilizes chromosome ends by inhibiting DNA damage response and DNA repair pathways. Telomere DNA can also adopt the “T-loop” conformation in which the 3’-overhang forms base pairs with a more proximal region of telomere repeats. This T-loop structure also suppresses the DNA damage response. Telomerase is a special reverse transcriptase comprised of a catalytic protein component (TERT) and a template RNA (TERC). ALT is a recombination-based telomere elongation pathway that resembles break-induced replication. In high-risk neuroblastoma, recurrent genomic aberrations are tightly linked to either the up-regulation of telomerase or activation of ALT. The telomerase pathway is primarily up-regulated by MYCN amplification or TERT promoter re-arrangement, whereas ALT is often activated by alterations in ATRX/DAXX/H3.3 and is associated with telomere replication stress, chromatin de-condensation, and elevated levels of telomere variant repeats