Molecular mechanism of nucleotide excision repair

摘要: From its very beginning, life has faced the fundamental problem that form in which genetic information is stored not chemically inert. DNA integrity challenged by damaging effect of numerous chemical and physical agents, compromizing function. To protect this Achilles heel, an intricate network repair systems evolved early evolution. One these nucleotide excision (NER), a highly versatile sophisticated damage removal pathway counteracts deleterious effects multitude lesions, including major types induced environmental sources. The most relevant lesions subject to NER are cyclobutane pyrimidine dimers (CPDs) (6-4) photoproducts (6-4PPs), two kinds injury produced shortwave UV component sunlight. In addition, bulky adducts eliminated process. Within divergent spectrum significant distortion helix appears be common denominator. Defects underlie extreme photosensitivity predisposition skin cancer observed with prototype syndrome xeroderma pigmentosum (XP). Seven XP complementation groups have been identified, representing distinct genes XPA–G (discussed detail below). last decade, all key factors cloned core ‘cut-and-paste’ reaction reconstituted vitro from purified components. Recently, XPC (complexed hHR23B) identified as DNA-damage sensor repair-recruitment factor. general transcription factor complex TFIIH, containing XPB XPD helicases, mediates strand separation at site lesion. XPA verifies open conformation crucial assembly remainder machinery. Replication protein A (RPA) stabilizes opened involved positioning XPG ERCC1–XPF endonucleases responsible for incisions around After damagecontaining oligonucleotide, typically 24–32 nucleotides length, replication fill remaining gap close it. Two modes can distinguished: over entire genome, referred global genome (GG–NER), transcription-blocking present transcribed strands, hence called transcription-coupled (TC–NER). Most harbor defects both subpathways. GG–NER dependent on activity mentioned above, GG– NER-specific XPC–hHR23B. rate strongly depends type For instance, 6-4PPs removed much faster than CPDs, probably because differences affinity location (accessibility) lesion influences vivo. TC–NER, detected elongating RNA polymerase II when it encounters Interestingly, disorder, Cockayne (CS), associated specific defect repair. identification (CS-A CS-B) shows least gene products specifically needed fast efficient strands. Phenotypically, CS pleiotropic condition characterized well severe neurological, developmental, premature aging features. symptoms seen even totally NERdeficient patients. additional suggest and/or proteins functions beyond NER. Also, non-NERspecific (such oxidative damage) stall elongation appear fashion, linking blocked multiple pathways. Intriguingly, some XP-B, XP-D, XP-G patients display features combined manifestations. Yet other XP-B XP-D individuals suffer CS-like brittle-hair trichothiodystrophy (TTD). This clinical conundrum points roles well. recent mouse model TTD linked mutations subunit dual functional TFIIH deficiencies basal underlying Thus, surprisingly wide heterogeneity due involved. 1Corresponding author. E-MAIL Hoeijmakers@gen.fgg.eur.nl; FAX 31 10 408 9468.