Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

Abstract

Achieving replicative immortality is a crucial step in tumorigenesis and requires both bypassing cell cycle checkpoints and the extension of telomeres, sequences that protect the distal ends of chromosomes during replication. In the majority of cancers this is achieved through the enzyme telomerase, however a subset of cancers instead utilize a telomerase-independent mechanism of telomere elongation-the Alternative Lengthening of Telomeres (ALT) pathway. Recent work has aimed to decipher the exact mechanism that underlies this pathway. To this end, this pathway has now been shown to extend telomeres through exploitation of DNA repair machinery in a unique process that may present a number of druggable targets. The identification of such targets, and the subsequent development or repurposing of therapies to these targets may be crucial to improving the prognosis for many ALT-positive cancers, wherein mean survival is lower than non-ALT counterparts and the cancers themselves are particularly unresponsive to standard of care therapies. In this review we summarize the recent identification of many aspects of the ALT pathway, and the therapies that may be employed to exploit these new targets.

Keywords: ATRX; G-quadruplexes; R-loops; Rad52; alternative lengthening of telomeres; break induced replication; telomeres.

Figure 1

An overview of the ALT process. Telomeres in ALT cancer cells undergo replicative stress potentially as a result of DNA secondary structure formation, including R-loops and G-quadruplexes. This results in the formation of a one ended double strand break. Damaged telomeres are clustered into ALT associated PML nuclear bodies, potentially mediated through the SUMOylation of Shelterin components, including TRF1 or TRF2. APBs constitute the site of recombination where telomeres are extended predominantly via a process of Rad52 dependent Break Induced Replication (BIR).