G4-DNA formation and chromatin remodelling are interdependent in human cells

Lawler, Nicholas B.; Ou, Arnold; King, Jessica J.; Evans, Cameron W.; Iyer, K. Swaminathan; Smith, Nicole M.

doi:10.1039/d3sc02533k

Cited by 3 publications

(1 citation statement)

References 49 publications

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“…This effect of G4 on DNA damage might be attributed to its ability to induce transcription-replication interactions and inhibit DNA replication 45,55,59,[61][62][63][64][65][66] . Furthermore, the formation of G4s regulates chromatin accessibility 55,56,67 and DNA methylation 68 . In addition to its function in promoting DNA damage, how G4s are linked to aging has not been determined.…”

Section: Introductionmentioning

confidence: 99%

A universal molecular mechanism driving aging

Jin,

Zheng,

Xiao

et al. 2024

Preprint

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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 andin vitromodels, 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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