Telomere Maintenance in Cancer: Beyond the Telomerase-versus-ALT Dualism

Abstract

Telomere maintenance is a defining requirement of malignant cells, which must counteract the progressive telomere attrition that otherwise drives replicative senescence. Two principal telomere maintenance mechanisms (TMM) have been characterized: the telomerase-dependent mechanism (TEL), which reactivates the telomerase ribonucleoprotein to add telomeric repeats, and the alternative lengthening of telomeres (ALT), a homologous-recombination-based, telomerase-independent pathway. Historically, these were framed as a mutually exclusive, binary choice inferred largely from canonical genetic lesions such as TERT promoter mutations and ATRX/DAXX loss. Drawing on mechanistic and structural studies of both pathways, large tumor cohorts that co-measure both mechanisms, and quantitative transcriptomic scoring, this review argues that tumor-level telomere maintenance state is better described as a multidimensional, context-dependent property, varying in the magnitude of each mechanism's activity, in the cellular composition of the tumor, and in temporal stability, than as a binary telomerase-versus-ALT label. This review synthesizes the molecular biology of telomere structure, the architecture and regulation of telomerase, and the recombination machinery underlying ALT, and surveys the current state of the art in telomere-directed therapy. Because telomere maintenance is dynamic rather than fixed, tumors capable of switching between or co-engaging maintenance mechanisms may exhibit reduced sensitivity to therapies targeting a single pathway, supporting TMM-stratified therapeutic assessment.