Abstract
A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telomere length heterogeneity. In this review, we focus on the mechanisms of the ALT pathway and potential clinical implications. We also discuss the characteristics of telomeres in PSCs, thereby shedding light on the therapeutic significance of telomere length regulation in age-related diseases and regenerative medicine.
Highlights
Telomeres consist of tandem TTAGGG repeats, ending with an approximate 50–500 nt G-rich3’-strand overhang [1,2]
Telomeres are enclosed by the shelterin protein complex, which contains the double-strand telomeric DNA binding factors TRF1 and TRF2, the TRF2-interacting protein RAP1, the bridging factor TIN2, and the telomeric ssDNA-binding protein POT1 and its direct interactor TPP1 [3]
In the other 15% of cancer cells, telomeres are maintained by an alternative lengthening of telomeres (ALT) mechanism, which mainly relies on homologous recombination (HR) between sister chromatids
Summary
Telomeres consist of tandem TTAGGG repeats, ending with an approximate 50–500 nt G-rich. 3’-strand overhang [1,2]. Shelterin proteins bind to the telomere structure and mediate the formation of a telomeric loop (T-loop) in which the single-strand 3’ overhang is concealed into a D-loop structure [4,5]. In stem cells and about 85% of cancer cells, the telomeres could be elongated by telomerase through adding TTAGGG repeats to the chromosome ends. In the other 15% of cancer cells, telomeres are maintained by an alternative lengthening of telomeres (ALT) mechanism, which mainly relies on homologous recombination (HR) between sister chromatids. This review focuses on the mechanisms of ALT in tumors and pluripotent stem cells as well as the implications for related potential therapies
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