Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0268140 (XPF)
 549 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Illudin S is a natural sesquiterpene drug with strong anti-tumour activity. Inside cells, unstable active metabolites of illudin cause the formation of as yet poorly characterised DNA lesions. In order to identify factors involved in their repair, we have performed a detailed genetic survey of repair-defective mutants for responses to the drug. We show that 90% of illudin's lethal effects in human fibroblasts can be prevented by an active nucleotide excision repair (NER) system. Core NER enzymes XPA, XPF, XPG, and TFIIH are essential for recovery. However, the presence of global NER initiators XPC, HR23A/HR23B and XPE is not required, whereas survival, repair and recovery from transcription inhibition critically depend on CSA, CSB and UVS, the factors specific for transcription-coupled NER. Base excision repair and non-homologous end-joining of DNA breaks do not play a major role in the processing of illudin lesions. However, active RAD18 is required for optimal cell survival, indicating that the lesions also block replication forks, eliciting post-replication-repair-like responses. However, the translesion-polymerase DNA pol eta is not involved. We conclude that illudin-induced lesions are exceptional in that they appear to be ignored by all of the known global repair systems, and can only be repaired when trapped in stalled replication or transcription complexes. We show that the semisynthetic illudin derivative hydroxymethylacylfulvene (HMAF, Irofulven), currently under clinical trial for anti-tumour therapy, acts via the same mechanism.
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PMID:Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription- and replication-coupled repair pathways. 1253 Oct 12

The transcription-coupled repair (TCR) pathway preferentially repairs DNA damage located in the transcribed strand of an active gene. To gain insight into the coupling mechanism between transcription and repair, we have set up an in vitro system in which we isolate an elongating RNA pol IIO, which is stalled in front of a cisplatin adduct. This immobilized RNA pol IIO is used as 'bait' to sequentially recruit TFIIH, XPA, RPA, XPG and XPF repair factors in an ATP-dependent manner. This RNA pol IIO/repair complex allows the ATP-dependent removal of the lesion only in the presence of CSB, while the latter does not promote dual incision in an XPC-dependent nucleotide excision repair reaction. In parallel to the dual incision, the repair factors also allow the partial release of RNA pol IIO. In this 'minimal TCR system', the RNA pol IIO can effectively act as a loading point for all the repair factors required to eliminate a transcription-blocking lesion.
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PMID:Initiation of DNA repair mediated by a stalled RNA polymerase IIO. 1640 75