期刊
GENES & DEVELOPMENT
卷 17, 期 20, 页码 2539-2551出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1131003
关键词
damage recognition; random assembly; cooperative binding; kinetic proofreading; xeroderma pigmentosum
资金
- NIGMS NIH HHS [GM32833, R01 GM032833] Funding Source: Medline
The cyclobutane thymine dimer is the major DNA lesion induced in human skin by sunlight and is a primary cause of skin cancer, the most prevalent form of cancer in the Northern Hemisphere. In humans, the only known cellular repair mechanism for eliminating the dimer from DNA is nucleotide excision repair. Yet the mechanism by which the dimer is recognized and removed by this repair system is not known. Here we demonstrate that the six-factor human excision nuclease recognizes and removes the dimer at a rate consistent with the in vivo rate of removal of this lesion, even though none of the six factors alone is capable of efficiently discriminating the dimer from undamaged DNA. We propose a recognition mechanism by which the low-specificity recognition factors, RPA, XPA, and XPC, act in a cooperative manner to locate the lesion and, aided by the kinetic proofreading provided by TFIIH, form a high-specificity complex at the damage site that initiates removal of thymine dimers at a physiologically relevant rate and specificity.
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