Non-canonical functions of telomerase in oxidative defense
Although organisms have evolved a set of stress responses to protect against adverse environmental conditions, protracted stressful conditions and long-term activation of the stress response negatively impact health and lifespan (Monaghan 2014). It is now broadly accepted that chronic stress and lifestyle factors such as oxidative stress, psychosocial stress, and improper health conditions can affect telomere dynamics (Epel et al. 2004; Kotrschal et al. 2007; Lin et al. 2012; Monaghan 2014; Korandová et al. 2018). DNA represents an important target of oxidative damage in cells, and the most common DNA damage caused by free oxygen radicals is oxidative modifications of DNA bases such as the formation of 8-oxoguanine. Oxidative DNA lesions are largely associated with single-strand breaks that are induced directly or as an intermediate step in the repair of oxidative base modifications. Due to their high content of guanine, telomeres are highly sensitive to oxidative damage and production of single-strand breaks that interfere with the replication fork and thus lead to telomere attrition (von Zglinicki 2002; Houben et al. 2007; Coluzzi et al. 2019).
An increasing body of evidence indicates that non-canonical telomerase functions participate in a variety of biological pathways related to the regulation of cell cycle, apoptosis, DNA repair, gene expression, or protection of cells against oxidative stress (Geserick et al. 2006; Saretzki 2009; Mukherjee et al. 2011; Ségal-Bendirdjian et al. 2019; Zheng et al. 2019). The impact of telomere biology on the cell functions under oxidative stress conditions is documented by the crosstalk between telomeres/telomerase and mitochondria (Zheng et al. 2019). It was discovered that mitochondrial dysfunction accelerates telomere shortening, implying that mitochondrial ROS (reactive oxygen species) may act as a determinant of telomere-dependent senescence (Liu et al. 2002; Passos et al. 2007), or that telomere shortening and dysfunction can lead to alterations in mitochondrial functioning (Guo et al. 2011; Sahin et al. 2011). It has also been reported that in response to oxidative stress induced by hyperoxia, 80-90% of TERT (the catalytic subunit of telomerase) is transported from the nucleus into mitochondria, ultimately resulting in a dramatic acceleration of telomere shortening. When the cellular conditions are shifted from hyperoxia back to normoxia, TERT is transported back to the nucleus, and telomere length is restored (Santos et al. 2006; Ahmed et al. 2008; Saretzki 2009). Telomerase may also exert a protective effect on mitochondrial functions. Under oxidative stress it binds to mitochondrial DNA, increases respiratory chain activity, and protects against oxidative stress-induced damage (Haendeler et al. 2009). Consistent with these observations, different tissues of the bank voleMyodes glareolus from the Chernobyl Exclusion Zone displayed reduced telomere length but upregulated telomerase activity. The upregulation of telomerase, in this case, appears to be associated with functions other than telomere maintenance, perhaps protection against a stressful environment (Kesäniemi et al. 2019).