Resolving Roadblocks to Telomere Replication.

The maintenance of genome stability in eukaryotic cells relies on accurate and efficient replication along each chromosome following every cell division. The terminal position, repetitive sequence, and structural complexities of the telomeric DNA make the telomere an inherently difficult region to replicate within the genome. Thus, despite functioning to protect genome stability mammalian telomeres are also a source of replication stress and have been recognized as common fragile sites within the genome. Telomere fragility is exacerbated at telomeres that rely on the Alternative Lengthening of Telomeres (ALT) pathway. Like common fragile sites, ALT telomeres are prone to chromosome breaks and are frequent sites of recombination suggesting that ALT telomeres are subjected to chronic replication stress. Here, we will review the features of telomeric DNA that challenge the replication machinery and also how the cell overcomes these challenges to maintain telomere stability and ensure the faithful duplication of the human genome.