Human Base Excision Repair for Preservation of Genomic Stability

نویسندگان

  • Mansour Akbari
  • Hans E. Krokan
  • Marit Otterlei
چکیده

Nuclear uracil-DNA glycosylase UNG2 has anestablished role in repair of U/A pairs resulting frommisincorporation of dUMP during replication. In anti-gen-stimulated B-lymphocytes UNG2 removes uracilfrom U/G mispairs as part of somatic hypermutationand class switch recombination processes. Usingantibodies specific for the N-terminal non-catalyticdomain of UNG2, we isolated UNG2-associated repaircomplexes (UNG2-ARC) that carry out short-patchand long-patch base excision repair (BER). Thesecomplexes contain proteins required for both typesof BER, including UNG2, APE1, POLb, POLd, XRCC1,PCNA and DNA ligase, the latter detected as activity.Short-patch repair was the predominant mechanismboth in extracts and UNG2-ARC from proliferating andless BER-proficient growth-arrested cells. Repair ofU/G mispairs and U/A pairs was completely inhibitedby neutralizing UNG-antibodies, but whereas addedrecombinant SMUG1 could partially restore repair ofU/G mispairs, it was unable to restore repair of U/Apairs in UNG2-ARC. Neutralizing antibodies to APE1and POLb, and depletion of XRCC1 strongly reducedshort-patch BER, and a fraction of long-patch repairwas POLb dependent. In conclusion, UNG2 is presentin preassembled complexes proficient in BER.Furthermore, UNG2 is the major enzyme initiatingBER of deaminated cytosine (U/G), and possibly thesole enzyme initiating BER of misincorporateduracil (U/A).

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تاریخ انتشار 2006