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The XPD subunit of TFIIH is required for transcription-associated but not DNA double-strand break-induced recombination in mammalian cells
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi. (Helleday)
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi. (Helleday)
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi. (Helleday)
2010 (engelsk)Inngår i: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 25, nr 6, s. 623-629Artikkel i tidsskrift (Annet vitenskapelig) Published
Abstract [en]

Mutations in the XPD gene can give rise to three phenotypically distinct disorders: xeroderma pigmentosum (XP),  trichothiodystrophy (TTD) or combined XP and Cockayne syndrome (CS) (XP/CS). The role of XPD in nucleotide excision repair explains the increased risk of skin cancer in XP patients, but not all the clinical phenotypes found in XP/CS or TTD patients. Here, we describe that the XPD defective UV5 cell line is impaired in transcription-associated recombination (TAR), which can be reverted by the introduction of the wild type XPD gene expressed from a vector. UV5 cells are defective in TAR, despite having intact transcription and homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Interestingly, we find reduced spontaneous HR in XPD defective cells, suggesting that transcription underlie a portion of spontaneous HR events. We also report that transcription-coupled repair (TCR) defective CSB cells, have a defect in TAR, but not in DSB-induced HR. However, the TAR defect may be associated with a general transcription defect in CSB deficient cells.  In conclusion, we show a novel role for the XPD protein in TAR, linking TAR with TCR.

sted, utgiver, år, opplag, sider
2010. Vol. 25, nr 6, s. 623-629
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-39035DOI: 10.1093/mutage/geq054OAI: oai:DiVA.org:su-39035DiVA, id: diva2:318048
Tilgjengelig fra: 2010-05-06 Laget: 2010-05-06 Sist oppdatert: 2022-02-24bibliografisk kontrollert
Inngår i avhandling
1. Transcription Associated Recombination in Mammalian Cells
Åpne denne publikasjonen i ny fane eller vindu >>Transcription Associated Recombination in Mammalian Cells
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

There is increasing evidence that the movement of the transcription machinery through DNA has profound effects on the genomic stability. One such example is a phenomenon known as Transcription Associated Recombination (TAR). Transcription enhances recombination levels to a high degree in all organisms studied, from bacteria to mammals. The underlying causes of the high recombination levels observed are unknown, as are the rationale for the rather riskyhazardous recombination event in this context. Recombination is not a risk-free event; there is e.g. the chancerisk for of loss of heterozygozity, which may eventually lead to tumour formation. So, why is TAR so ubiquitous? This thesis deals with the factors inducing TAR, trying to elucidate the mechanisms catalyzing this event. The proteins involved in executing TAR are unknown in mammals, and one of the aims of this thesis havehas been to investigate the role of well-known DNA repair proteins in TAR. In order to do so, cell lines deficient in crucial DNA repair proteins were stably transfected with a novel recombination construct. Transcription can be controlled over this recombination construct, enabling the detection of transcription associated recombination. We found that TAR is dependent on replication and that inhibition of transcription elongation had no further effect on TAR levels in our system. Further, we found that TAR employs a recombination pathway mechanistically separate from the recombination pathway induced by DNA double strand breaks. This pathway is dependent on BRCA2, a protein required for homologous recombination, but independent of the RAD51 paralog XRCC2. In subsequent studies, we found that the XPD subunit of the combined transcription and repair factor TFIIH is required for TAR, but is dispensable for DNA DSB repair by HR. We went on to investigate the connection between HR repair of UV damages and transcription and found that repair of UV damages requires transcription, but not via the transcription-coupled repair pathway. In conclusion, we found that TAR operates by a recombination pathway separate from DNA double strand break induced recombination. We found a connection with stalled replication, and revealed several of the proteins required for TAR in mammals.

sted, utgiver, år, opplag, sider
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2010. s. 62
HSV kategori
Forskningsprogram
molekylärgenetik
Identifikatorer
urn:nbn:se:su:diva-38931 (URN)978-91-7447-079-6 (ISBN)
Disputas
2010-06-03, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.Tilgjengelig fra: 2010-05-11 Laget: 2010-05-04 Sist oppdatert: 2022-03-18bibliografisk kontrollert

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