Abstract
Simple SummaryThe segmentation of eukaryotic genomes into discrete linear chromosomes requires processes to solve several major biological problems, including prevention of the chromosome ends being recognized as DNA breaks and compensation for the shortening that occurs when linear DNA is replicated. A specialized set of six proteins, collectively referred to as shelterin, is involved in both of these processes, and mutations in several of these are now known to be involved in cancer. Here, we focus on Protection of Telomeres 1 (POT1), the shelterin protein that appears to be most commonly involved in cancer, and consider the clinical significance of findings about its biological functions and the prevalence of inherited and acquired mutations in the POT1 gene.Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.
Highlights
Telomeres are specialized nucleoprotein structures that cap the ends of linear chromosomes, consisting of a complex of DNA, RNA and proteins
The TPP1–Protection of Telomeres 1 (POT1) heterodimer may control telomerase-dependent telomere lengthening through recruitment of CST, which is a negative regulator of telomerase: depletion of CST proteins or overexpression of a dominant-negative mutant of CTC1 may result in telomere lengthening in some telomerase-positive human cell lines [40,53,54,55]
Germline and somatic POT1 mutations have been identified in a range of cancer types
Summary
Telomeres are specialized nucleoprotein structures that cap the ends of linear chromosomes, consisting of a complex of DNA, RNA and proteins. Telomeres control cellular replicative potential, because, in most somatic cells of multicellular eukaryotes, telomeric DNA gradually shortens with each cell cycle, due, in part, to the end-replication problem, whereby the linear ends of chromosomes are incompletely replicated [4,5] and, in part, due to the enzymatic processing of the C-rich strand [6,7]. The upregulation of a TMM is a core event in the acquisition of unlimited replicative potential (i.e., cellular immortality), one of the hallmarks of cancer [17]. Since telomeres are associated both with genome stability and cellular immortalization, the study of telomere biology is important for understanding cancer risk, diagnosis, prognosis and the outcome of therapy, and for devising new therapies. We summarize what is known about the normal function of the POT1 protein, and the nature of the POT1 alterations in human cancer, and consider the insights this provides into cancer biology and potential clinical implications
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