The Human Ligase IIIα-XRCC1 Protein Complex Performs DNA Nick Repair after Transient Unwrapping of Nucleosomal DNA

• Published in: The Journal of biological chemistry Vol. 292; no. 13; pp. 5227 - 5238
• Main Authors: Cannan, Wendy J., Rashid, Ishtiaque, Tomkinson, Alan E., Wallace, Susan S., Pederson, David S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.03.2017; American Society for Biochemistry and Molecular Biology
• Subjects: base excision repair (BER); Binding Sites; Chromatin; DNA - metabolism; DNA and Chromosomes; DNA enzyme; DNA Ligase ATP; DNA Ligases - metabolism; DNA Ligases - physiology; DNA repair; DNA Repair - physiology; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; histone; Histones - metabolism; Humans; Nucleosomes - genetics; X-ray Repair Cross Complementing Protein 1; base excision repair (BER); DNA enzyme; histone; chromatin; DNA repair
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.736728

Reactive oxygen species generate potentially cytotoxic and mutagenic lesions in DNA, both between and within the nucleosomes that package DNA in chromatin. The vast majority of these lesions are subject to base excision repair (BER). Enzymes that catalyze the first three steps in BER can act at many sites in nucleosomes without the aid of chromatin-remodeling agents and without irreversibly disrupting the host nucleosome. Here we show that the same is true for a protein complex comprising DNA ligase IIIα and the scaffolding protein X-ray repair cross-complementing protein 1 (XRCC1), which completes the fourth and final step in (short-patch) BER. Using in vitro assembled nucleosomes containing discretely positioned DNA nicks, our evidence indicates that the ligase IIIα-XRCC1 complex binds to DNA nicks in nucleosomes only when they are exposed by periodic, spontaneous partial unwrapping of DNA from the histone octamer; that the scaffolding protein XRCC1 enhances the ligation; that the ligation occurs within a complex that ligase IIIα-XRCC1 forms with the host nucleosome; and that the ligase IIIα-XRCC1-nucleosome complex decays when ligation is complete, allowing the host nucleosome to return to its native configuration. Taken together, our results illustrate ways in which dynamic properties intrinsic to nucleosomes may contribute to the discovery and efficient repair of base damage in chromatin.