原创力文档regulation of nucleotide excision repair by uv-ddb prioritization of damage recognition to internucleosomal dna调节核苷酸切除修复uv-ddb优先级的损伤识别internucleosomal dna.pdfVIP
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regulation of nucleotide excision repair by uv-ddb prioritization of damage recognition to internucleosomal dna调节核苷酸切除修复uv-ddb优先级的损伤识别internucleosomal dna
Regulation of Nucleotide Excision Repair by UV-DDB:
Prioritization of Damage Recognition to
Internucleosomal DNA
1. 1. 2 3 3 1
Jia Fei , Nina Kaczmarek , Andreas Luch , Andreas Glas , Thomas Carell , Hanspeter Naegeli *
¨ ¨
1 Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland, 2 German Federal Institute for Risk Assessment (BfR), Department of
Product Safety Center for Alternatives to Animal Testing, Berlin, Germany, 3 Department of Chemistry and Biochemistry, Ludwig-Maximilian-University Munich, Munich,
Germany
Abstract
How tightly packed chromatin is thoroughly inspected for DNA damage is one of the fundamental unanswered questions in
biology. In particular, the effective excision of carcinogenic lesions caused by the ultraviolet (UV) radiation of sunlight
depends on UV-damaged DNA-binding protein (UV-DDB), but the mechanism by which this DDB1-DDB2 heterodimer
stimulates DNA repair remained enigmatic. We hypothesized that a distinctive function of this unique sensor is to
coordinate damage recognition in the nucleosome repeat landscape of chromatin. Therefore, the nucleosomes of human
cells have been dissected by micrococcal nuclease, thus revealing, to our knowledge for the first time, that UV-DDB
associates preferentially with lesions in hypersensitive, hence, highly accessible internucleosomal sites joining the core
particles. Surprisingly, the accompanying CUL4A ubiquitin ligase activity is necessary to retain the xeroderma pigmentosum
group C (XPC) partner at such internucleosomal repair hots
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