ALTernative Telomere Maintenance and Cancer

Abstract

Activation of a telomere maintenance mechanism (TMM) is permissive for replicative immortality and a hallmark of human cancer. While most cancers rely on reactivation of telomerase, a significant fraction utilizes the recombination dependent alternative lengthening of telomeres (ALT) pathway. ALT is enriched in tumors of mesenchymal origin, including those arising from bone, soft tissue, and the nervous system, and usually portends a poor prognosis. Recent insights into the mechanisms of ALT are uncovering novel avenues to exploit vulnerabilities and may facilitate clinical development of ALT detection assays and personalized treatment decisions based on TMM status. Treatments targeting ALT may hold promise for a broadly applicable therapeutic modality specific to mesenchymal lineage tumors, something that has thus far remained elusive.

Keywords: alternative lengthening of telomeres; cancer; recombination; telomere.

Figure 1, Key Figure

Updated model of alternative lengthening of telomeres (ALT) (A). A permissive environment for telomere recombination likely occurs through telomeric chromatin changes, such as those mediated by mutations in ATRX/DAXX/H3.3, altered histone dynamics, changes in DNA and histone modifications, and decreased nucleosome density. In this permissive environment, DNA double strand breaks (DSBs) initiate ALT recombination. The source of these break signals may come from replication stress due to chromatin changes, TERRA mediated R-loops, or G-quadruplex (G4) structures. Endonuclease activity or telomere uncapping could also lead to DSB signals. Excessive RPA and ATR signaling may create a permissive environment for recombination and/or signal the presence of DSBs. DSB signals lead to a Rad51 and Hop2-Mnd1 mediated homology search and capture of a homologous sequence (telomere or internal genomic site) by the 3’ or 5’ end of the recipient telomere. The NR2C/F family of nuclear receptors can facilitate the proximity of homologous sequences. DNA synthesis and resolution of synapsed telomeres occur by unknown mechanisms. Ultimately, this process leads to elongation of telomeres or targeted telomere insertion (TTI) at genomic sites. (B) The model of ALT provides a framework for therapeutically targeting essential steps including: (1) DSB response, (2) Homology search, (3) DNA synthesis, and (4) Resolution. DNA damaging agents could cause hyperactivity of the DSB response and lead to toxic recombination. ATR inhibitors can function to inhibit DSB responses or DNA synthesis events. Other potential ways to attack synthesis include DNA polymerase, PCNA, and BLM inhibitors. G4 stabilizing agents could be used to cause replication stress.

Figure 2

Telomere maintenance mechanism (TMM) profiling of alternative lengthening of telomeres (ALT) may have clinical utility for diagnosis, prognosis, and treatment of ALT-positive tumors. Diagnosis could be determined through the C-circle (CC) assay with or without quantitative PCR (qPCR) techniques to increase sensitivity and specificity. Additionally, mutational profiling of ATRX/DAXX/H3.3 may predict ALT activity in some tumor types. These tests may facilitate monitoring for tumor formation in patients with syndromes predisposing to ALT-positive tumors or for tumor dynamics or recurrence of established ALT-positive tumors. Since ALT has prognostic value in many settings, identification of ALT could enable more informed treatment decisions. Finally, TMM profiling may allow for personalized telomere-targeted therapies. In particular, treatments to decrease or increase ALT activity could exploit vulnerabilities present in ALT-positive tumors and lead to selective cell killing. ATR inhibitors represent a promising therapeutic strategy. By targeting ALT, we may in principle benefit patients with ALT-positive tumors, including those that have escaped telomerase inhibitors through ALT activation.