GCOE外国人研究者等セミナー

Xue ZHANG (個体機能学講座 細胞機能学研究室(田中研究室))

演題 Genotype-Phenotype Relationship in Xeroderma Pigmentosum, Trichothiodystrophy and Cockayne Syndrome
演者 Dr.Kenneth.H. Kraemer

(DNA Repair Section, Basic Research Laboratory, Center for Cancer Research,National Cancer Institute,NIH)
日時

2009年 12月15日(火) 14:00-15:00

場所 吹田キャンパス アネックス棟 2Fセミナー室


※クリックで写真拡大

報告

Nucleotide excision repair (NER) is a remarkably flexible DNA repair pathway capable of eliminating a wide range of DNA lesions that caused by environmental genotoxins and cancer chemotherapeutic agents. Two subpathways in NER are known. One is global genome NER (GGR), which removes DNA damage from the nuclear genome. The core NER pathway is then recruited and removes the lesion through sequential steps of strand unwinding, incision in a number of bases on either side of the lesion, excision of the lesion as part of a short single-stranded oligonucleotide, and filling in of the resultant gap using semi-conservative DNA replication factors and the non-damaged complementary strand as template. The other NER sub-pathway, transcription-coupled NER (TCR), removes DNA damage that blocks ongoing transcription in the transcribed DNA strand of active genes. TCR differs from GGR only in the manner of lesion recognition. It is triggered by blockage of RNA polymerase II at adducted sites along the transcribed strand, following the binding of the damage sites by CSA and CSB proteins in order to recruit the core NER pathway (This process is carried by XPC/HR23B in GGR), which then, in the identical manner as GGR, completely restores the integrity of the DNA. 
Mutations in one of the many genes involved in the NER process have severe consequences. Three well-known genetic disorders, xeroderma pigmentosum (XP group A-G, and Variant), Cockayne syndrome (CS) and trichothiodystrophy (TTD) have been illustrated as results of NER deficiency. They comprise several complementation groups and patients exhibit multiple symptoms such as neural/developmental abnormalities and high incidence of cancer whereas hyper UV sensitivity is a hallmark. 
In today's seminar, Dr Kraemer provided us with large amount of information on clinical phenotypes of XP, CS and TTD patients in relations with their mutations on certain positions of certain genes. There is a complex relationship between the clinical diseases and the molecular defects in NER. Patients with one of several clinical diseases may have inherited a defect in one of several different NER genes. Since the NER pathway functions in sequence, a defect in one portion of the pathway impairs the function of the subsequent steps. Thus patients with XP can have defects in XPA, XPB, XPC, XPD, XPE, XPF or XPG genes. Conversely, different defects in one gene may lead to different clinical diseases. Thus different mutations in the XPD gene may lead to one of six different clinical disorders: XP, XP neurological disease, TTD, the XP/CS complex, XP/TTD complex or a severe form of CS known as COFS (cerebral, ocular, facial, skeletal syndrome). 
In the case of XP and TTD, for one example, patients with XP have a 1,000-fold increase in UV-induced skin cancers while TTD patients, despite mutations in the same genes, XPD or XPB, are cancer-free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV-induced 6-4 photoproducts (6-4PP) in their DNA and low levels of the basal transcription factor, TFIIH. It is found that XPC protein was rapidly localized in all cells but was redistributed in TTD and normal cells by 3 hr post-irradiation, while remained localized in XP cells at 24-hr post-irradiation. In XP cells recruitment of other NER proteins was also delayed and persisted at 24 hr. It is considered that in XP persistence of NER proteins at sites of unrepaired DNA damage is associated with greatly increased skin cancer risk possibly by blockage of translesion DNA synthesis. In contrast, in TTD, low levels of unstable TFIIH proteins do not accumulate at sites of unrepaired photoproducts and may permit normal translesion DNA synthesis without increase of skin cancer.
The varied clinical phenotypes in XP, CS and TTD may result from altered interactions of the defective proteins with other proteins that control growth, development or cancer susceptibility. Notably, only some of the proteins are currently associated with clinical diseases. Furthermore, the clinical phenotypes associated with the known disorders are quite varied. Thus, it seems possible that defects in these proteins might underlie other rare diseases.



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