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Researchers here describe a G-quadruplex-related mechanism operating across diverse species that contributes to epigenetic change following cell replication, leading to the Hayflick limit on replication and subsequent cell death or cell senescence. G-quadruplexes form in telomeric regions at the ends of chromosomes, and their contributions to genomic structure, epigenetics, and aging are far from fully understood.
Insofar as the mechanism described in this paper is operating in organismal aging, it is worth bearing in mind that aging is accompanied by a reduction in stem cell activity, meaning a reduced supply of replacement somatic cells for tissues. Thus the average somatic cell in a tissue starts to be one that is more cycles of replication removed from the original daughter somatic cell created by a stem cell, and will be more affected by any replication-related mechanism.
Perhaps the more interesting result is the connection between this mechanism and a number of accelerated aging conditions, including Werner syndrome, in which mutations lead to an impairment of G-quadruplex removal. This implies that cell replication in affected individuals produces greater dysfunction than usual, leading to more cellular senescence and faster aging.
How cell replication ultimately results in aging and the Hayflick limit are not fully understood. Here we show that clock-like accumulation of DNA G-quadruplexes (G4s) throughout cell replication drives conserved aging mechanisms. G4 stimulates transcription-replication interactions to delay genome replication and impairs DNA re-methylation and histone modification recovery, leading to loss of heterochromatin. This creates a more permissive local environment for G4 formation in subsequent generations.
As a result, G4s gradually accumulate on promoters throughout mitosis, driving clock-like DNA hypomethylation and chromatin opening. In patients and in vitro models, loss-of-function mutations in the G4-resolving enzymes WRN, BLM and ERCC8 accelerate the erosion of the epigenomic landscape around G4. G4-driven epigenomic aging is strongly correlated with biological age and is conserved in yeast, nematodes, insects, fish, rodents, and humans. Our results revealed a universal molecular mechanism of aging and provided mechanistic insight into how G-quadruplex processor mutations drive premature aging.
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