title: Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base excision repair.
abstract: Each day, approximately 20,000 oxidative lesions form in the DNA of every nucleated human cell. The base excision repair (BER) enzymes that repair these lesions must function in a chromatin milieu. We have determined that the DNA glycosylase hNTH1, apurinic endonuclease (APE), and DNA polymerase β (Pol β), which catalyze the first three steps in BER, are able to process their substrates in both 601- and 5S ribosomal DNA (rDNA)-based nucleosomes. hNTH1 formed a discrete ternary complex that was displaced by the addition of APE, suggesting an orderly handoff of substrates from one enzyme to the next. In contrast, DNA ligase IIIα-XRCC1, which completes BER, was appreciably active only at concentrations that led to nucleosome disruption. Ligase IIIα-XRCC1 was also able to bind and disrupt nucleosomes containing a single base gap and, because of this property, enhanced both its own activity and that of Pol β on nucleosome substrates. Collectively, these findings provide insights into rate-limiting steps that govern BER in chromatin and reveal a unique role for ligase IIIα-XRCC1 in enhancing the efficiency of the final two steps in the BER of lesions in nucleosomes.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405, USA.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Odell
authors.forename: Joy-El
authors.initials: JE
authors.lastname: Barbour
authors.forename: Drew L
authors.initials: DL
authors.lastname: Murphy
authors.forename: Julie A
authors.initials: JA
authors.lastname: Della-Maria
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
authors.forename: Alan E
authors.initials: AE
authors.lastname: Tomkinson
authors.forename: Susan S
authors.initials: SS
authors.lastname: Wallace
authors.forename: David S
authors.initials: DS
authors.lastname: Pederson
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000378:metabolism; D006801:Humans; D047331:Lytechinus / Q000235:genetics; D009707:Nucleosomes / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species; D000076105:X-ray Repair Cross Complementing Protein 1; D014981:Xenopus / Q000235:genetics; D029867:Xenopus Proteins
chemical_list: D004268:DNA-Binding Proteins; D009707:Nucleosomes; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D029867:Xenopus Proteins; D004247:DNA; D019951:DNA Polymerase beta; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human