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DNA end joining becomes less efficient and more error-prone during cellular senescence.
Andrei Seluanov1, David Mittelman, Olivia M Pereira-Smith
1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Summary
Cellular senescence impairs DNA double-strand break (DSB) repair, specifically end joining efficiency. This age-related decline in DNA repair contributes to genomic instability and may increase cancer risk in older adults.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Somatic mutation accumulation is linked to aging.
- Genomic instability increases with age, suggesting impaired DNA double-strand break (DSB) repair.
- DSB repair has not been extensively studied in relation to cellular senescence.
Purpose of the Study:
- To investigate the efficiency and fidelity of DSB repair in young, presenescent, and senescent human fibroblasts.
- To determine if cellular senescence affects DNA end joining pathways.
Main Methods:
- Utilized a fluorescent reporter substrate to assess DSB repair in transfected normal human fibroblasts.
- Compared DNA repair efficiency and analyzed end junction sequences across different cellular ages (young, presenescent, senescent).
Main Results:
- End joining efficiency was reduced up to 4.5-fold in presenescent and senescent cells compared to young cells.
- Senescent cells exhibited more error-prone end joining with extended deletions, unlike precise ligation in young cells.
- The capacity for microhomology-mediated end joining was diminished in senescent cells.
Conclusions:
- Cellular senescence leads to inefficient and error-prone DNA end joining.
- Age-related decline in end joining may contribute to genomic instability.
- Altered end joining pathways in senescent cells could underlie age-associated genomic instability and cancer risk.