Reparative system function

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Reparative system function

Eukaryotic cells have multiple mechanisms for repairing damaged DNA. DNA repair pathways can be divided into five categories: direct repair, base excision repair (BER), nucleotide excision repair (NER), double-strand break repair (DSB), and repair of interstrand cross-links. The specialized DNA glycosylases and AP endonucleases of BER act on spontaneous and induced DNA alterations caused by hydrolysis, oxygen free radicals, and simple alkylating agents. NER utilizes many proteins (including the XP proteins in humans) to remove the major UV-induced photoproducts from DNA, as well as other types of modified nucleotides. Different DNA polymerases and ligases are used to complete the separate pathways.

MMR removes mispaired bases resulting from replication errors, recombination between imperfectly matched sequences and deamination of 5-methyl-cytosine. DNA replication past a mismatched base pair would result in a point mutation. MMR is essential for maintenance of repeated sequences, as mutations in MMR genes are associated with a substantial destabilization of microsatellites and microsatellite instability increases with aging in humans. Results showed a decline in MMR with increasing in vitro age.

Excision repair removes lesions that affect only one DNA strand, which permits excision of the lesion and subsequent use of the complementary strand to fill the gap. BER corrects small DNA alterations that do not distort the overall structure of DNA helix, such as oxidized bases, or incorporation of uracil. Excision repair is critically important for repairing base damage induced by reactive oxygen species. BER is initiated by DNA glycosylases, which cleave N-glycosylic bond of damaged bases leaving apurinic/apyrimidinic site (AP site). The abasic site is then processed by AP endonuclease (APE1) leaving a single-stranded gap. The gap is filled by DNA polymerase β and ligated by DNA ligase. Measuring the levels and kinetics of AP sites following DNA damage in nuclear DNA showed that senescent human fibroblasts as well as leukocytes from old donors have higher basal level of AP sites than young cells. A significant decrease in the mitochondrial incision activity of oxidized guanine (8-oxoG) DNA glycosylase, uracil DNA glycosylase and the endonuclease III homolog was found in the brains of old mice, whereas smaller changes were observed in nuclear incision activity. Multiple evidence indicates that BER undergoes age-related changes, which are likely to contribute to the accumulation of oxidative DNA lesions and mutations with aging.

NER removes short DNA oligonucleotides containing a damaged base. NER recognizes bulky lesions caused by carcinogenic compounds, and covalent linkages between adjacent pyrimidines resulting from UV exposure. Studies of NER in cells or tissues from young and old individuals consistently showed a decline of NER capacity with increasing age. Recent studies have shown that multiple mutations in the NER genes result in dramatically accelerated aging phenotypes. The progeroid phenotypes caused by NER defects were associated with characteristic changes of the global transcription patterns. Similar changes were seen in wild type mice in response to stress and during aging. It is tempting to speculate that the decline of NER function that occurs in normal individuals contributes to the onset of aging.

A DSB is the most lethal of all DNA lesions. If unrepaired, a DSB leads to loss of chromosome segments and threatens the survival of the cell. Equally detrimental to the organism are misrepaired DSBs that destabilize the genome and lead to genomic rearrangements. Genomic rearrangements become common in aging organisms ultimately leading to deregulation of transcription and malignancies. DSBs in DNA are repaired by two major mechanisms: homologous recombination (HR) and nonhomologous end joining (NHEJ). The level of Ku, which is a protein responsible for recognition and binding to DSBs, has been shown to decline markedly in the testis of aging rats, and lymphocytes from human donors of increasing age. Furthermore, intracellular distribution of Ku differed between young and senescent cells. In young cells, Ku was distributed throughout the cytoplasm and the nucleus, and translocated to the nucleus in response to γ-irradiation. In contrast, in senescent cells, all Ku was localized in the nucleus, so no additional Ku can be brought into the nucleus to repair DNA damage. Ku may remain at the damage sites and shortened telomeres, which cannot be repaired by DNA repair machinery in senescent cells. Impaired nuclear targeting and DNA binding activities of Ku have been reported in peripheral blood mononuclear cells of aged humans. Thus, decline of NHEJ with age may be caused by reduced availability and altered regulation of Ku. Disruption of genes involved in DSB repair often leads to premature aging phenotypes.