Mechanisms of telomere maintenance and associated therapeutic vulnerabilities in malignant gliomas

Abstract

A majority of cancers (~85%) activate the enzyme telomerase to maintain telomere length over multiple rounds of cellular division. Telomerase-negative cancers activate a distinct, telomerase-independent mechanism of telomere maintenance termed alternative lengthening of telomeres (ALT). ALT uses homologous recombination to maintain telomere length and exhibits features of break-induced DNA replication. In malignant gliomas, the activation of either telomerase or ALT is nearly ubiquitous in pediatric and adult tumors, and the frequency with which these distinct telomere maintenance mechanisms (TMMs) is activated varies according to genetically defined glioma subtypes. In this review, we summarize the current state of the field of TMMs and their relevance to glioma biology and therapy. We review the genetic alterations and molecular mechanisms leading to telomerase activation or ALT induction in pediatric and adult gliomas. With this background, we review emerging evidence on strategies for targeting TMMs for glioma therapy. Finally, we comment on critical gaps and issues for moving the field forward to translate our improved understanding of glioma telomere maintenance into better therapeutic strategies for patients.

Keywords: ATRX; TERT; alternative lengthening of telomeres; gliomas; telomeres.

Figure 1.

Regulatory elements of the TERT promoter region and cancer-specific mechanisms of activation. (A) Simplified schematic of the TERT promoter showing a proximal ETS for ETS-like transcription factor binding. (B) Mechanisms and location of cancer-associated TERT promoter mutations and the binding of -124C>T mutation by a GABPβ1L heterotetrameric transcription factor. (C) Mechanism by which TERT promoter ETS duplications is permissive to heterotetrameric GABPβ1L binding and promoter activation. (D) Illustration of genomic structural variants upstream of TERT that lead to increased TERT mRNA expression. Created with Biorender.com.

Figure 2.

Model of break-induced telomere replication. ALT-mediated telomere maintenance occurs via a process that resembles break-induced replication. In the presence of glioma-associated genetic alterations (eg, mutations in ATRX, SMARCAL1, or H3F3A) stalled replication forks have an increased propensity to degenerate into DNA DSBs. Strand-invasion and homology search create a telomeric D-loop, which is followed by de novo telomere synthesis by a break-induced replisome consisting of replication factor C, proliferation cell nuclear antigen (PCNA), and Polδ. The D-loop then undergoes dissolution by the BTR complex (BLM, Top3A, and RMI) resulting in telomere extension or is resolved by the SLX3-SLX1-MUS81 complex, resulting in crossover without telomere extension. The complex molecular orchestration of BIR of telomeres and the adaptive balance between replication fork stalling/collapse and telomere length maintenance present a targetable therapeutic vulnerability in ALT-positive gliomas. Created using Biorender.com.