Telomeres protect genomic DNA through various mechanisms. Because the classical chromosomal DNA replication machinery cannot copy the DNA completely out to the extreme ends of the linear chromosomes, progressive attrition (shortening) of chromosome ends will occur during cell divisions, until the critically shortened telomeres elicit responses that prevent further cell divisions. In eukaryotes the cellular ribonucleoprotein enzyme telomerase, by adding telomeric DNA repeat sequences to the ends of chromosomes, can elongate them to compensate for their attrition (1). Therefore, sufficient telomerase action is required for long-term telomere maintenance and protection.
Single-gene inactivating mutations in telomerase genes in humans, and in mouse models of telomerase deficiency, cause progressive, excessive telomere shortening, with consequent loss of telomere capping/protection (2). The resultant human pathologies include developing certain cancers: hematological (such as leukemias and myelodysplastic syndromes), squamous-cell skin cancers and gastrointestinal cancers. These and other well-documented pathologies in humans and mouse are consistent with attrition of telomeres, apparently progressively from their ends inwards, being the primary cause underlying such cancer development. However, results from yeast model systems also open the possibility that additional mechanisms, besides such progressive telomere end shortening, may contribute to the pathologies that develop upon telomerase deficiency.
We reported that budding yeast mother cells, even very early after telomerase inactivation (ETI) showed transient DNA damage response (DDR) episodes, stochastically altered cell-cycle dynamics, and accelerated mother cell aging that includes mitochondrial changes (3). Strikingly, these all occurred many cell generations before the onset of critical telomere shortening. The data indicated that telomerase is continuously required to fully resolve transient episodes of telomeric DNA replication stress that normally occur in these dividing cells. Furthermore, disrupting the DDR adaptor proteins in ETI budding yeast cells caused synthetic lethality, and we reported that the normally-occurring telomeric DNA replication stress is resolved by telomerase activity and the DDR in parallel pathways (4). Hence, if telomerase is insufficient, viability becomes dependent on intact DDR components. These findings have implications for how genomic instability is instigated in settings of insufficient telomerase.