TY - JOUR
T1 - Nucleosome disruption by DNA Ligase III-XRCC1 promotes efficient base excision repair
AU - Odell, Ian D.
AU - Barbour, Joy El
AU - Murphy, Drew L.
AU - Della-Maria, Julie A.
AU - Sweasy, Joann B.
AU - Tomkinson, Alan E.
AU - Wallace, Susan S.
AU - Pederson, David S.
PY - 2011/11
Y1 - 2011/11
N2 - 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 ratelimiting 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.
AB - 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 ratelimiting 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.
UR - http://www.scopus.com/inward/record.url?scp=83255192188&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=83255192188&partnerID=8YFLogxK
U2 - 10.1128/MCB.05715-11
DO - 10.1128/MCB.05715-11
M3 - Article
C2 - 21930793
AN - SCOPUS:83255192188
SN - 0270-7306
VL - 31
SP - 4623
EP - 4632
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 22
ER -