Role of POT1 in Human Cancer

Abstract

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.

Keywords: POT1; alternative lengthening of telomeres; cancer; genomic instability; mutation; shelterin; telomerase; telomere; telomere length.

Figure 1

Shelterin complex and Protection of Telomeres 1 (POT1) protein. (A) Telomeres are composed of tandem repetitive TTAGGG sequences that are predominantly double-stranded (ds) but terminate in a single stranded (ss) 3′-overhang of the G-rich strand [6,36]. Telomeres are shielded with the shelterin complex, consisting of the TRF1, TRF2, RAP1, TIN2, TPP1 and POT1 proteins. POT1 binds to the TPP1 protein and to telomeric ss DNA through its C- and N-termini, respectively, and controls the sequence at the ds/ss junction. The human POT1 protein contains three oligonucleotide/oligosaccharide-binding (OB) fold domains, namely OB1-3, and OB3 has an embedded Holliday junction resolvase-like (HJRL) domain. (B) POT1 splice variants and their functions [21,29,37]

Figure 2

Burden of non-benign POT1 mutations across cancer types. The prevalence of POT mutations defined as neither “presumed benign” nor “benign” was investigated in 62,368 tumors. The figure shows the POT1 mutation burden in some tumor categories that included more than 50 cases (data from [65]). The number in brackets indicate the total number of cases for each cancer type.

Figure 3

Proposed roles of POT1 mutations in development of cancer. We speculate here that the effects of POT1 mutations differ according to the telomerase status of the cancer progenitor cells, with genomic instability and perhaps the activation of alternative lengthening of telomeres (ALT) being the predominant contributor to oncogenesis in cells that are telomerase-negative and therefore less able to counteract the deleterious effects of the POT1 mutation on telomere cap function, and with increased telomere length being the predominant contributor when the progenitor cells have telomerase activity.