Alternative Lengthening of Telomeres and Mediated Telomere Synthesis

Abstract

Telomeres are DNA–protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin, and ALT also frequently occurs during experimental cellular immortalization of mesenchymal cells. ALT is a process that relies on homologous recombination (HR) to elongate telomeres. However, some processes in the ALT mechanism remain poorly understood. Here, we review the most recent understanding of ALT mechanisms and processes, which may help us to better understand how the ALT pathway is activated in cancer cells and determine the potential therapeutic targets in ALT pathway-stabilized tumors.

The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients

“…Enrichment or amplification of DNA fragments containing ALT-TFs followed by sequencing or other readouts 61 could further improve sensitivity and scalability, thus complementing current liquid biopsy methods 62 , 63 . Overall, detection of ALT-TFs in blood and cell-free DNA represents a method for liquid biopsy analysis, with implications for early detection, patient stratification, disease monitoring and treatment selection 64 .…”

Ku–DNA binding inhibitors modulate the DNA damage response in response to DNA double-strand breaks

“…Ku–DNA binding inhibition could play an effective role in DNA-PK independent-Ku mechanisms, like telomere metabolism and maintenance where Ku has been demonstrated to support telomerase catalyzed telomere length maintenance ( 40 , 41 ). One could then envision less Ku-DBi sensitivity in cells that maintain telomeres via the alternative lengthening of telomeres (ALT) pathway compared to telomerase positive cancers ( 42 , 43 ).…”

Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics

“…27 The alternative lengthening of telomeres (ALT) mechanism elongates the attrited telomeres based on the DNA homologous recombination (HR) pathways. 28 ALT is characterized by highly heterogeneous telomere lengths, frequent exchanges between telomeres and sister chromatids, existence of ALT associated promyelocytic leukemia bodies (APBs) and extra-chromosomal repeated telomeric DNA circles. 29 ALT is highly prevalent in cancers derived from mesenchymal tissues, viz neuroendocrine system, soft tissues, and peripheral and central nervous systems.…”