DNA repair

Damage to DNA can result from mutations such as replication errors, and incorporation of mismatched nucleotides (substitution errors – transitions and transversions). DNA damage can also result from unintentional and intentional stressor environmental stimuli such as oxygen radicals, hydroxyl radicals, ionizing or ultraviolet radiation, toxins, alkylating agents, and chemotherapy agents, particularly anti-cancer drugs.

Damaged bases can be corrected by simple in situ chemical reversal of the defect, but excision-repair processes predominate. These important DNA repair mechanisms take advantage of the fact that DNA is double-stranded and that complementary sequences should match on both strands. So, if damage is confined to one strand, the damage can be accurately repaired by excision and replacement with DNA synthesized with the undamaged complementary strand acting as template. All organisms, prokaryotic and eukaryotic, utilize at least three enzymatic excision-repair mechanisms: base excision repair, mismatch repair, and nucleotide excision repair. See also targeted genetic repair and trans-splicing ribozymes and therapeutics.

dNTP: "In eukaryotes, DNA damage elicits a multifaceted response that includes cell cycle arrest, transcriptional activation of DNA repair genes, and, in multicellular organisms, apoptosis."

The DNA-repair enzymes have the capability of searching through vast tracts of DNA to uncover subtle structural anomalies. The human repair enzyme 8-oxoguanine glycosylase (hOGG1) efficiently removes 8-oxoguanine (oxoG), a damaged guanine (G) base containing an extra oxygen atom, while it ignores undamaged bases. The structure of hOGG1 bound to undamaged DNA, reveals a unique strategy that permits faithful removal of damaged bases which do 'fit' into the oxoG slot at the enzyme's active site, while normal G bases do not.

Also: exogenous nucleobase rescue of abasic substitutions :

Anders Jahres medisinske priser: modified: "To date, at least six distinct pathways of DNA repair have been discovered, comprising nucleotide excision repair, base excision repair, mismatch repair, repair by recombination (homologous and nonhomologous end rejoining), damage tolerance pathways (polymerase bypass) and different damage reversal mechanisms, involving close to 200 genes in human cells. "

PLoS Biology: Three New Phases of Repairing DNA Damage in E. coli: "E. coli SOS response has been used to study DNA repair for decades, and a great deal is known about how the more than 30 genes involved in the response function. Two proteins figure prominently in this response. The LexA protein acts as a repressor and inhibits the expression of SOS genes under normal conditions; in the event of DNA damage, the protein RecA inactivates the LexA repressor by enhancing its autocleavage into two fragments, which initiates the SOS response. "

Discovery Of Why Some DNA Repair Fails: Significant For Huntington's Disease And Colon Cancer: modified "Dr. McMurray's group studied a specific mismatch repair protein Msh2-Msh3 and found a paradox: Instead of helping repair DNA damage, under certain conditions, Msh2-Msh3 was actually harming the cell. Msh2-Msh3 did this when it arrived at the wrong place at the wrong time and bound to a specific portion of DNA (CAG-hairpin). This accident of binding at the CAG-hairpin altered the biochemical activity of Msh2-Msh3. This change in biochemical activity, in turn, promoted DNA expansion -- rather than repair -- and changed the function of Msh2-Msh3 from friend of DNA to foe by allowing damaged DNA to go unrepaired. Without DNA repair, mutations accumulate that lead to disease."

MOLECULAR BIOLOGY: ON DNA-REPAIR ENZYMES: "hOGG1 makes extensive contacts with the orphaned cytosine base, which ensures that oxoG is removed only when in the appropriate base-pairing context. Although extensive biophysical and structural studies intimate that there are general features of damaged bases that signal their presence to repair enzymes, the steps involved in finding damaged bases in a sea of normal ones are still unclear. Most mechanisms invoke the enzyme sliding or hopping along the DNA duplex until a damaged site is detected. A particularly intriguing question is whether normal bases are also extruded from the helix during the search process."


No comments: