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 rDNA-based nucleosomes. hNTH1 formed a discrete ternary complex that was displaced by the addition of APE, suggesting an orderly hand-off 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.

Polymerases:

Topics:

Mutational Analysis, Modulators/Inhibitors, Kinetic Parameters, Accessory Proteins/Complexes, Enzyme Substrate Interactions

Status:

new topics/pols set partial results complete validated

Results:

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