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The following is a summary of “Faulty Gap Filling in Nucleotide Excision Repair Leads to Double-Strand Break Formation in Senescent Cells,” published in the January 2025 issue of Dermatology by Suzuki et al. 

Researchers conducted a retrospective study to examine the change in repair efficiency of UV-induced pyrimidine dimers in replicatively senescent fibroblasts and explore the mechanisms of DNA damage repair impairment due to aging.  

They analyzed replicative senescent fibroblasts for UV-induced pyrimidine dimer repair. The incision efficiency of oligonucleotides with UV lesions was assessed, and the gap-filling process was evaluated. The release of repair proteins, including xeroderma pigmentosum group G, proliferating cell nuclear antigen, and replication protein A, was monitored. Double-strand break formation was investigated through ataxia telangiectasia-mutated phosphorylation and 53BP1 foci formation. The contribution of MRE11 nuclease activity was studied using pharmacological inhibitors.  

The results showed the incision efficiency of UV lesion-containing oligonucleotides was consistent across cell doubling levels, but gap filling was impaired in senescent cells. Delayed release of xeroderma pigmentosum group G, proliferating cell nuclear antigen, and replication protein A indicated disrupted DNA polymerase progression. Persistent single-stranded DNA in senescent cells likely converted to double-strand breaks, causing ataxia telangiectasia-mutated phosphorylation and 53BP1 foci formation. Phosphorylated histone H2AX (γ-H2AX) induction was observed mainly in the G1 phase, not the S phase, suggesting replication stress-independent double-strand breaks. MRE11 accumulated early at damaged sites but failed to release in senescent cells. Pharmacological studies indicated that MRE11 contributed to the enlargement of single-stranded DNA gaps, facilitating double-strand break formation.  

Investigators concluded that aging impairs DNA repair in senescent cells, characterized by delayed repair protein release, increased single-stranded DNA, and enhanced double-strand break formation, with MRE11 contributing to this impairment by facilitating gap enlargement and promoting double-strand break formation, ultimately contributing to genomic instability in aging cells. 

Source: sciencedirect.com/science/article/abs/pii/S0022202X24017299