Molecular mechanisms of DNA damage recognition for mammalian nucleotide excision repair.
For faithful DNA repair, it is crucial for cells to locate lesions precisely within the vast genome. In the mammalian global genomic nucleotide excision repair (NER) pathway, this difficult task is accomplished through multiple steps, in which the xeroderma pigmentosum group C (XPC) protein complex plays a central role. XPC senses the presence of oscillating 'normal' bases in the DNA duplex, and its binding properties contribute to the extremely broad substrate specificity of NER. Unlike XPC, which acts as a versatile sensor of DNA helical distortion, the UV-damaged DNA-binding protein (UV-DDB) is more specialized, recognizing UV-induced photolesions and facilitating recruitment of XPC. Recent single-molecule analyses and structural studies have advanced our understanding of how UV-DDB finds its targets, particularly in the context of chromatin. After XPC binds DNA, it is necessary to verify the presence of damage in order to avoid potentially deleterious incisions at damage-free sites. Accumulating evidence suggests that XPA and the helicase activity of transcription factor IIH (TFIIH) cooperate to verify abnormalities in DNA chemistry. This chapter reviews recent findings about the mechanisms underlying the efficiency, versatility, and accuracy of NER.
Biosignal Research Center, Kobe University, Kobe, Hyogo 657-8501, Japan. Electronic address: ksugasawa@garnet.kobe-u.ac.jp.
Kaoru
K
Sugasawa
D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016678:Genome; D006801:Humans; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D051758:Transcription Factor TFIIH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D051758:Transcription Factor TFIIH; C086984:XPC protein, human; D004247:DNA
Chromatin; DNA damage recognition; Nucleotide excision repair; TFIIH; UV-DDB; XPA; XPC