The enigma of excessively long telomeres in cancer: lessons learned from rare human POT1 variants

Abstract

The discovery that rare POT1 variants are associated with extremely long telomeres and increased cancer predisposition has provided a framework to revisit the relationship between telomere length and cancer development. Telomere shortening is linked with increased risk for cancer. However, over the past decade, there is increasing evidence to show that extremely long telomeres caused by mutations in shelterin components (POT1, TPP1, and RAP1) also display an increased risk of cancer. Here, we will review current knowledge on germline mutations of POT1 identified from cancer-prone families. In particular, we will discuss some common features presented by the mutations through structure-function studies. We will further provide an overview of how POT1 mutations affect telomere length regulation and tumorigenesis.

Figure 1.

Rare germline variants in POT1 identified in familial cancers. (A) Schematic structure of human POT1 protein and conserved domains. OB1 and OB2 folds of POT1 mediating telomeric ss-DNA binding are colored in blue. The C-terminal OB3 and embedded HJRL domain mediating TPP1 binding are colored in red. The positions of variants identified in familial cancers are shown as pins on top of the protein. The taller pins represent the mutations that have been identified more than once. (B) Table of deleterious germline mutations identified in the POT1 gene.

Figure 2.

Impact of rare POT1 variants on telomere length, telomere DNA replication, genome integrity, and cancer. (A) Regulation of telomere length homeostasis by POT1. Wild-type POT1 together with TPP1 functions to protect telomere ends and to modulate telomerase access to 3’ ssDNA. The POT1-TPP1 complex both negatively and positively regulates telomerase recruitment and processivity. The CST complex facilitates telomere DNA replication and terminates telomerase action. (B) Rare POT1 variants lose the ability to protect telomeres through different mechanisms, shown in the boxes. Ultimately, cells undergo progressive telomere elongation, which further exacerbates replication burden and telomere fragility, consequently contributing to genome instability and cancer. Also, excessively long telomeres may allow bypass of the replicative senescence checkpoint and promote tumorigenesis.