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Transcriptional healing Transcription-coupled DNA repair and aging: from molecule to mouse-model

Projectomschrijving

DNA wordt continue beschadigd door o.a. zonlicht (UV), chemicaliën en vreemd genoeg ook door onze eigen stofwisseling. DNA schade verstoort o.a. het transcriptie proces, waardoor cellen sneller dood gaan wat tot versnelde veroudering kan leiden. Transcriptie-gekoppelde DNA reparatie (TCR) speelt een belangrijke rol in het voorkomen van veroudering door DNA schade. Cockayne syndroom patiënten hebben een aangeboren TCR-defect waardoor extreem snelle veroudering plaatsvindt. Echter een andere groep patiënten met overgevoeligheid voor UV-straling, UV-sensitief syndroom (UVSSA), hebben een vergelijkbaar TCR-defect maar vertonen geen verouderingsverschijnselen. Recent hebben wij het gen verantwoordelijk voor UVSSA geïdentificeerd. In dit project wordt de functie en wisselwerking tussen de verschillende TCR eiwitten onderzocht. Kennis over TCR zal leiden tot een beter begrip van de rol die DNA schade speelt in veroudering en bijdragen aan de ontwikkeling van therapieën en interventies.

Producten

Titel: SUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair
Auteur: van Cuijk, Loes, van Belle, Gijsbert J., Turkyilmaz, Yasemin, Poulsen, Sara L., Janssens, Roel C., Theil, Arjan F., Sabatella, Mariangela, Lans, Hannes, Mailand, Niels, Houtsmuller, Adriaan B., Vermeulen, Wim, Marteijn, Jurgen A.
Magazine: Nature Communications
Titel: Human ISWI complexes are targeted by SMARCA5 ATPase and SLIDE domains to help resolve lesion-stalled transcription
Auteur: Aydin, O. Z., Marteijn, J. A., Ribeiro-Silva, C., Rodriguez Lopez, A., Wijgers, N., Smeenk, G., van Attikum, H., Poot, R. A., Vermeulen, W., Lans, H.
Magazine: Nucleic Acids Research
Titel: A ubiquitylation site in Cockayne syndrome B required for repair of oxidative DNA damage, but not for transcription-coupled nucleotide excision repair
Auteur: Ranes, Michael, Boeing, Stefan, Wang, Yuming, Wienholz, Franziska, Menoni, Hervé, Walker, Jane, Encheva, Vesela, Chakravarty, Probir, Mari, Pierre-Olivier, Stewart, Aengus, Giglia-Mari, Giuseppina, Snijders, Ambrosius P., Vermeulen, Wim, Svejstrup, Jesper Q.
Magazine: Nucleic Acids Research
Titel: DNA damage-induced replication stress results in PA200-proteasome-mediated degradation of acetylated histones
Auteur: Mandemaker, Imke K, Geijer, Marit E, Kik, Iris, Bezstarosti, Karel, Rijkers, Erikjan, Raams, Anja, Janssens, Roel C, Lans, Hannes, Hoeijmakers, Jan HJ, Demmers, Jeroen AA, Vermeulen, Wim, Marteijn, Jurgen A
Magazine: EMBO Reports
Titel: Live-cell analysis of endogenous GFP-RPB1 uncovers rapid turnover of initiating and promoter-paused RNA Polymerase II
Auteur: Steurer, Barbara, Janssens, Roel C., Geverts, Bart, Geijer, Marit E., Wienholz, Franziska, Theil, Arjan F., Chang, Jiang, Dealy, Shannon, Pothof, Joris, van Cappellen, Wiggert A., Houtsmuller, Adriaan B., Marteijn, Jurgen A.
Magazine: Proceedings of the National Academy of Sciences
Titel: An immunoaffinity purification method for the proteomic analysis of ubiquitinated protein complexes.
Auteur: Schwertman P, Bezstarosti K, Laffeber C, Vermeulen W, Demmers JA, Marteijn JA.
Magazine: Analytical Biochemistry
Titel: ISWI chromatin remodeling complexes in the DNA damage response
Auteur: Aydin, Ö.Z. , Vermeulen, W and Lans, H.
Magazine: Cell Cycle
Titel: TTDA: Big impact of a small protein
Auteur: Theil, Arjan F., Hoeijmakers, Jan H.J., Vermeulen, Wim
Magazine: Experimental Cell Research
Titel: UVSSA and USP7, a new couple in transcription-coupled DNA repair.
Auteur: Schwertman P, Vermeulen W, Marteijn JA
Magazine: Chromosoma
Titel: Understanding nucleotide excision repair and its roles in cancer and ageing
Auteur: Marteijn, Jurgen A., Lans, Hannes, Vermeulen, Wim, Hoeijmakers, Jan H. J.
Magazine: Nature
Titel: Ubiquitin at work: The ubiquitous regulation of the damage recognition step of NER
Auteur: van Cuijk, Loes, Vermeulen, Wim, Marteijn, Jurgen A.
Magazine: Experimental Cell Research
Titel: Amplification of unscheduled DNA synthesis signal enables fluorescence-based single cell quantification of transcription-coupled nucleotide excision repair
Auteur: Wienholz, Franziska, Vermeulen, Wim, Marteijn, Jurgen A.
Magazine: Nucleic Acids Research
Titel: Bidirectional coupling of splicing and ATM signaling in response to transcription-blocking DNA damage
Auteur: Tresini, Maria, Marteijn, Jurgen A., Vermeulen, Wim
Magazine: RNA Biology
Titel: Trichothiodystrophy causative TFIIEß mutation affects transcription in highly differentiated tissue
Auteur: Theil, Arjan F, Mandemaker, Imke K, van den Akker, Emile, Swagemakers, Sigrid M A, Raams, Anja, Wüst, Tatjana, Marteijn, Jurgen A, Giltay, Jacques C, Colombijn, Richard M, Moog, Ute, Kotzaeridou, Urania, Ghazvini, Mehrnaz, von Lindern, Marieke, Hoeijmakers, Jan H J, Jaspers, Nicolaas G J, van der Spek, Peter J, Vermeulen, Wim
Magazine: Human Molecular Genetics
Titel: The core spliceosome as target and effector of non-canonical ATM signalling
Auteur: Tresini, Maria, Warmerdam, Daniël O., Kolovos, Petros, Snijder, Loes, Vrouwe, Mischa G., Demmers, Jeroen A. A., van IJcken, Wilfred F. J., Grosveld, Frank G., Medema, René H., Hoeijmakers, Jan H. J., Mullenders, Leon H. F., Vermeulen, Wim, Marteijn, Jurgen A.
Magazine: Nature
Titel: DNA damage-induced histone H1 ubiquitylation is mediated by HUWE1 and stimulates the RNF8-RNF168 pathway
Auteur: Mandemaker, I. K., van Cuijk, L., Janssens, R. C., Lans, H., Bezstarosti, K., Hoeijmakers, J. H., Demmers, J. A., Vermeulen, W., Marteijn, J. A.
Magazine: Scientific Reports
Titel: The transcription-coupled DNA repair-initiating protein CSB promotes XRCC1 recruitment to oxidative DNA damage
Auteur: Menoni, Hervé, Wienholz, Franziska, Theil, Arjan F, Janssens, Roel C, Lans, Hannes, Campalans, Anna, Radicella, J Pablo, Marteijn, Jurgen A, Vermeulen, Wim
Magazine: Nucleic Acids Research

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Samenvatting van de aanvraag

Age related diseases and discomfort have become a major social and medical issue due to the still increasing lifespan. Therefore it is highly relevant to understand the biological processes that counteract this phenomenon. Increasing evidence suggests that transcription-coupled repair (TCR) is important to prevent DNA damage-induced aging. TCR is a specialized DNA repair systems that recognizes and repairs stalled transcription complexes at DNA lesions. If not repaired properly, these lesions form a physical block for transcription elongating complexes. Lesion-stalled transcription cause cellular apoptosis and senescence, eventually resulting in DNA damage-induced aging. TCR-deficiency is associated with two disorders: Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS). Despite a similar cellular defect both syndromes exhibit strikingly distinct symptoms: CS individuals display severe developmental and premature aging features, whereas UVSS patients express much milder features, restricted to UV-hypersensitivity. It is suggested that this wide variety in TCR-deficient phenotype is caused by the differential sensitivity towards oxidative DNA lesions, originating from endogenous metabolites. CS patients are sensitive for oxidative lesions, while UVSS patients are not, while both patient groups are equally sensitive to UV induced damage. The recent identification in our lab of the causative gene for UVSS puts us in the unique position to specifically study both the UV as well as the oxidative damage induced TCR. To understand the causal relationship between damage-induced aging and TCR function, it is thus important to known how different TCR factors deal with stalled transcription on oxidative or UV-induced lesions. Our objective is to understand how TCR functions and how the different factors protect organisms against DNA damage-induced aging. To provide insight into how different inherited defects in TCR exhibit such a wide variety in phenotype, we will combine in a systems biology approach state-of-the-art genetic, imaging, biochemical, genomic and proteomic tools. The powerful technology to generate genetically defined mouse models will be fully exploited to study the role of key TCR factors in the whole organism. Further development and application of quantitative live cell imaging and biochemical and quantitative proteomic tools will be instrumental to dissect the molecular mechanism of TCR. This knowledge will finally lead to improved diagnosis and will aid the development of novel tools for drug design and evaluation and establishment of a framework for translational research, which is not only relevant for CS, but also for other progeroid syndromes and natural aging.

Onderwerpen

Kenmerken

Projectnummer:
91212132
Looptijd: 100%
Looptijd: 100 %
2013
2018
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. W. Vermeulen
Verantwoordelijke organisatie:
Erasmus MC