248
The study is devoted to the influence of aging on the repair processes of ultraviolet-induced DNA damage in fibroblasts, with a focus on the mechanisms of repair disorders and genomic instability.
The researchers analyzed replicatively senescent fibroblasts to assess their ability to repair UV-induced pyrimidine dimers. They found that the efficiency of cutting oligonucleotides with UV lesions remained stable regardless of the stage of cell doubling, whereas DNA gap filling was impaired in senescent cells. Impaired release of key repair proteins, such as xeroderma pigmentosum group G, nuclear antigen of proliferating cells, and replication protein A, indicated reduced DNA polymerase activity.
Senescent cells showed accumulation of single-stranded DNA, which was likely transformed into double-strand breaks. This was confirmed by phosphorylation of the ataxia telangiectasia protein (ATM) and the formation of foci of the 53BP1 protein. This phenomenon was associated with the induction of phosphorylated histone H2AX (?-H2AX), which was mainly observed in the G1 phase, indicating the occurrence of double-strand breaks independent of replication stress.
Particular attention was paid to the activity of the nuclease MRE11, which accumulated early at sites of damage but was not released in senescent cells. The use of pharmacological inhibitors confirmed that MRE11 plays a role in increasing single-strand DNA breaks and promoting the formation of double-strand breaks. This, in turn, contributed to the increase in genomic instability characteristic of senescent cells.
The authors concluded that replicative senescence disrupts DNA repair processes, as evidenced by delayed release of repair proteins, accumulation of single- and double-strand breaks, and MRE11 activity, which catalyzes genomic instability. This finding highlights the key role of DNA repair disorders in the progression of age-related cellular changes and their instability.
