RT Journal Article
SR Electronic
T1 A universal molecular mechanism driving aging
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.01.06.574476
DO 10.1101/2024.01.06.574476
A1 Jin, Wan
A1 Zheng, Jing
A1 Xiao, Yu
A1 Ju, Lingao
A1 Chen, Fangjin
A1 Fu, Jie
A1 Jiang, Hui
A1 Zhang, Yi
YR 2024
UL http://biorxiv.org/content/early/2024/01/06/2024.01.06.574476.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.