Researchers have discovered a mechanism involving G-quadruplexes that contributes to epigenetic change, leading to the Hayflick limit on replication and subsequent cell death or cell senescence across diverse species. These G-quadruplexes form in telomeric regions at the ends of chromosomes, and their impact on genomic structure, epigenetics, and aging is not fully understood.
The mechanism described in the paper operates in organismal aging, where a reduction in stem cell activity accompanies aging, leading to a reduced supply of replacement somatic cells for tissues. This results in somatic cells being more affected by any replication-related mechanism.
A noteworthy result is the connection between this mechanism and accelerated aging conditions, such as Werner syndrome, where mutations impair G-quadruplex removal, 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.
