Review Volume 7, Issue 12 pp 1050—1065

DNA repair and aging: the impact of the p53 family

Figure 2. DNA repair systems in mammals. (Left) SSBs repair mechanisms: BER. Different damage-specific glycosylases (such as OGG1 or UNG) recognize and excise the damaged base (here shown in green). The resulting AP site is target of the endonuclease APE1 that physically creates the SSB. In the short-patch sub-pathway, only one nucleotide is replaced by Polβ while the gap is sealed by XRCC1-ligase IIIα. On the other hand, during the long-patch sub-pathway, Polδ/ε synthesize 2-8 nucleotides and FEN1 removes the 5′ flap DNA, whereas the ligation step is carried out by the complex PCNA-ligase I; NER: The initial step of lesion detection (here shown in yellow) is the only difference between GG-NER and TC-NER and it is executed by XPC/XPE or by CSB/CSA, respectively. After this step, the DNA helix is locally opened by the helicases subunits of TFIIH that allow the damage verification by XPA. The endonucleases XPF and XPG finally perform a dual incision flanking the lesion, thus releasing a 25-30 nucleotides oligomer. The single-strand gap is filled by the polymerases δ and ε, while the final nick is sealed by DNA ligase I and the complex XRCC1-ligase IIIα. (Right) DSBs repair mechanisms: HR: This process is initiated by the resection of the DSB by the nuclease activity of the MRN complex, in order to generate 3′ ssDNA tails. The protruding DNA is rapidly coated by RPA protein to keep it unwound; then Rad51, supported by several other factors such as BRCA1, BRCA2 and Rad52, drives the formation of the nucleoprotein filament on the ssDNA coated with RPA. RAD51 also mediates the strand invasion and the search for homologous sequences of the nucleoprotein complex. The process ends with the resolution of Holliday junction; NHEJ: The heterodimer Ku70/Ku86 rapidly senses the presence and binds to free dsDNA ends, thus recruiting and activating the DNA-PK catalytic subunit. The kinase activity of DNA-PK is required to activate the nuclease activity of Artemis, necessary to process ends before joining. The Ligase IV and its cofactor XRCC4 finally perform the ligation step. XLF and XLS are recently established members of this pathway whose functions are still under debate.