Abstract
Telomere maintenance is one of the mechanisms ensuring indefinite divisions of cancer and stem cells. Good understanding of telomere maintenance mechanisms (TMM) is important for studying cancers and designing therapies. However, molecular factors triggering selective activation of either the telomerase dependent (TEL) or the alternative lengthening of telomeres (ALT) pathway are poorly understood. In addition, more accurate and easy-to-use methodologies are required for TMM phenotyping. In this study, we have performed literature based reconstruction of signaling pathways for the ALT and TEL TMMs. Gene expression data were used for computational assessment of TMM pathway activities and compared with experimental assays for TEL and ALT. Explicit consideration of pathway topology makes bioinformatics analysis more informative compared to computational methods based on simple summary measures of gene expression. Application to healthy human tissues showed high ALT and TEL pathway activities in testis, and identified genes and pathways that may trigger TMM activation. Our approach offers a novel option for systematic investigation of TMM activation patterns across cancers and healthy tissues for dissecting pathway-based molecular markers with diagnostic impact.
Highlights
Telomeres perform protective functions at the ends of linear eukaryotic chromosomes
In order to address the current lack of signaling pathway representations of telomere maintenance mechanisms (TMMs), we have performed a literature search to identify genes involved in telomerase dependent (TEL) and/or alternative lengthening of telomeres (ALT) TMMs and to define their interaction partners and functional role (Figure 1)
The ALT pathway is represented through a series of branches describing DNA damage and assembly of associated promyelocytic leukemia bodies (APBs) bodies, which promote separation of one of the telomere strands and invasion to another telomeric template from sister chromatids, other chromosomes or extra-chromosomal telomeric sequences, followed by DNA polymerase delta assisted telomere synthesis and ultimate processing of Holliday junctions, which are formed during strand invasion (Figure 1A; Henson et al, 2002; Pickett and Reddel, 2015; Jia-Min Zhang et al, 2019; Sobinoff and Pickett, 2020)
Summary
Telomeres perform protective functions at the ends of linear eukaryotic chromosomes. They constitute one of the basic molecular factors conditioning the ability of cells to divide. Excessive cell divisions lead to incomplete reconstitution of telomeres resulting in telomere shortening and loss of proper structure of telomeric ends (Blackburn, 1991; Chow et al, 2012; Martínez and Blasco, 2015). Proliferative cells, such as cancer and stem cells, may utilize mechanisms for preserving telomere ends despite many rounds of divisions (Greenberg, 2005). These are known as telomere maintenance mechanisms (TMMs; Hug and Lingner, 2006). The TEL pathway is more commonly occurring in stem cells and the majority of cancers, while ALT is mostly activated in tumors
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