Cellular senescence induces replication stress with almost no affect on DNA replication timing.

Area of Science:

• Cellular biology
• Molecular biology
• Genetics

Background:

• Organismal aging involves physiological decline, with cellular senescence contributing significantly.
• Senescence, a cell cycle arrest, can be triggered by telomere shortening (replicative senescence) or oncogene activation.
• Replication stress, characterized by stalled DNA replication forks, impacts genome stability and is linked to diseases.

Purpose of the Study:

• To investigate the relationship between replication stress and DNA replication timing during senescence.
• To understand how the spatiotemporal program of DNA replication is affected by senescence progression.

Main Methods:

• Studied DNA replication programs in proliferative and pre-senescent cells using single DNA fiber combing.
• Employed origin mapping via sequencing of short nascent strands.
• Utilized genome-wide profiling of replication timing (TRT).

Main Results:

• Progression into replicative senescence (RS) reduced replication fork rates and activated dormant origins, indicating replication stress.
• Replication timing (RT) was globally unaffected by replication stress during entry into senescence, except for a delay in CREB5 gene RT.
• RT alterations in aging are not a direct consequence of senescence progression.

Conclusions:

• Replication timing is largely resistant to replication stress during cellular senescence.
• Senescence progression involves replication stress but does not globally alter DNA replication timing.
• Findings clarify the interplay between aging, senescence, and DNA replication programs.