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Accumulation of DNA damage with age in the mammalian brain has been reported during the period 1971 to 2008 in at least 29 studies. [29] This DNA damage includes the oxidized nucleoside 8-oxo-2'-deoxyguanosine (8-oxo-dG), single-and double-strand breaks, DNA-protein crosslinks and malondialdehyde adducts (reviewed in Bernstein et al. [29 ...
In eukaryotes, ATP-dependent chromatin remodeling complexes and histone-modifying enzymes are two factors that act to accomplish this remodeling process after DNA damage occurs. [60] Further DNA repair steps, involving multiple enzymes, usually follow. Some of the first responses to DNA damage, with their timing, are described below.
Nucleotide excision repair (NER) is a particularly important excision mechanism that removes DNA damage induced by ultraviolet light (UV). UV DNA damage results in bulky DNA adducts — these adducts are mostly thymine dimers and 6,4-photoproducts. Recognition of the damage leads to removal of a short single-stranded DNA segment that contains ...
After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR.
Most of the DNA repair deficiency diseases show varying degrees of "accelerated aging" or cancer (often some of both). [37] But elimination of any gene essential for base excision repair kills the embryo—it is too lethal to display symptoms (much less symptoms of cancer or "accelerated aging"). [38]
An arsenal of DNA repair mechanisms exists to repair various forms of damaged DNA and minimize genomic instability. Most DNA repair mechanisms require an intact DNA strand as template to fix the damaged strand. DNA damage prevents the normal enzymatic synthesis of DNA by the replication fork.
In the human hematopoietic stem cell compartment DNA damage accumulates with age. [90] In healthy humans after 50 years of age, chronological age shows a linear association with DNA damage accumulation in blood mononuclear cells. [91] Genome-wide profiles of DNA damage can be used as highly accurate predictors of mammalian age. [92]
Endogenous DNA damages occur frequently including about 50 double-strand DNA breaks per cell cycle [69] and about 10,000 oxidative damages per day (see DNA damage (naturally occurring)). During repair of double-strand breaks many epigenetic alterations are introduced, and in a percentage of cases epigenetic alterations remain after repair is ...