Abstract
Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication stress-induced DNA damage of telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) can be considered a common origin of senescence in vitro, with consequences on ageing in vivo. Unexpectedly, mtDNA and telDNA share common features indicative of a high degree of replicative stress, such as G-quadruplexes, D-loops, RNA:DNA heteroduplexes, epigenetic marks, or supercoiling. To avoid these stresses, both compartments use similar enzymatic strategies involving, for instance, endonucleases, topoisomerases, helicases, or primases. Surprisingly, many of these replication helpers are active at both telDNA and mtDNA (e.g., RNAse H1, FEN1, DNA2, RecQ helicases, Top2α, Top2β, TOP3A, DNMT1/3a/3b, SIRT1). In addition, specialized telomeric proteins, such as TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component), or TIN2 (shelterin complex), shuttle from telomeres to mitochondria, and, by doing so, modulate mitochondrial metabolism and the production of ROS, in a feedback manner. Hence, mitochondria and telomeres use common weapons and cooperate to resist/prevent replication stresses, otherwise producing common consequences, namely senescence and ageing.
Highlights
Senescence and AgeingSenescence is defined as a stress-induced durable cell cycle arrest
protein 1 (POT1) stimulates WRN and BLM helicase activity to linearize G4 [28] and limits their formation by direct binding [42]. The silencing of these telomere replication-helper factors results in replication stress characterized by multiple telomeric signals and sister-telomere associations during metaphase, a phenotype defined as fragile telomere
Because one of the main differences between chromosomes and mitochondrial chromosoma is the absence of telomeres, it is surprising to see how telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) share common properties and maintenance mechanisms
Summary
Senescence is defined as a stress-induced durable cell cycle arrest These stresses are of different origin, such as metabolic compromise and DNA damage, and are propagated in vivo by secretory (senescence-associated secretory phenotype (SASP)) and inflammatory pathways (for review, see [1]). MMF sustains a high level of reactive oxygen species (ROS) production, participating in the DNA damage senescence pathway (see below). This last category is mainly associated with telomere dysfunction and replicative senescence. The first involves p53 stabilization (for instance, following DNA damage), and p21CIP1 transcription This CDKI (cyclin-dependent kinase inhibitor) in turn inhibits CDK4/6 and pRb phosphorylation, blocking the entry into the S-phase. We will hereafter focus our discussion on the contribution of telomeres and mitochondria to senescence and ageing, and present unexpected common molecular mechanisms
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