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Dive into the research topics where Christoffel Dinant is active.

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Featured researches published by Christoffel Dinant.


Journal of Cell Biology | 2009

Heterochromatin protein 1 is recruited to various types of DNA damage

Martijn S. Luijsterburg; Christoffel Dinant; Hannes Lans; Jan Stap; Elzbieta Wiernasz; Saskia Lagerwerf; Daniël O. Warmerdam; Michael Lindh; Maartje C. Brink; Jurek Dobrucki; Jacob A. Aten; Maria Fousteri; Gert Jansen; Nico P. Dantuma; Wim Vermeulen; Leon H.F. Mullenders; Adriaan B. Houtsmuller; Pernette J. Verschure; Roel van Driel

Heterochromatin protein 1 (HP1) family members are chromatin-associated proteins involved in transcription, replication, and chromatin organization. We show that HP1 isoforms HP1-α, HP1-β, and HP1-γ are recruited to ultraviolet (UV)-induced DNA damage and double-strand breaks (DSBs) in human cells. This response to DNA damage requires the chromo shadow domain of HP1 and is independent of H3K9 trimethylation and proteins that detect UV damage and DSBs. Loss of HP1 results in high sensitivity to UV light and ionizing radiation in the nematode Caenorhabditis elegans, indicating that HP1 proteins are essential components of DNA damage response (DDR) systems. Analysis of single and double HP1 mutants in nematodes suggests that HP1 homologues have both unique and overlapping functions in the DDR. Our results show that HP1 proteins are important for DNA repair and may function to reorganize chromatin in response to damage.


Journal of Cell Biology | 2010

The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage

Dorthe Helena Larsen; Catherine Poinsignon; Thorkell Gudjonsson; Christoffel Dinant; Mark Payne; Flurina J Hari; Jannie Rendtlew Danielsen; Patrice Menard; Jette Christensen Sand; Manuel Stucki; Claudia Lukas; Jiri Bartek; Jens S. Andersen; Jiri Lukas

The CHD4 helicase is identified as a new component of the genome surveillance machinery in a proteomic screen for factors enriched on chromatin after ionizing radiation (see also related paper by Smeenk et al. in this issue).


Cell | 2012

TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

Thorkell Gudjonsson; Matthias Altmeyer; Velibor Savic; Luis Ignacio Toledo; Christoffel Dinant; Merete Grøfte; Jirina Bartkova; Maria Poulsen; Yasuyoshi Oka; Simon Bekker-Jensen; Niels Mailand; Beate Neumann; Jean-Karim Hériché; Robert F. Shearer; Darren N. Saunders; Jiri Bartek; Jiri Lukas; Claudia Lukas

Histone ubiquitylation is a prominent response to DNA double-strand breaks (DSBs), but how these modifications are confined to DNA lesions is not understood. Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. Thus, regulatory and proteolytic ubiquitylations are wired in a self-limiting circuit that promotes histone ubiquitylation near the DNA lesions but at the same time counteracts its excessive spreading to undamaged chromosomes. We provide evidence that this mechanism is vital for the homeostasis of ubiquitin-controlled events after DNA breakage and can be subverted during tumorigenesis.


Journal of Cell Science | 2007

Activation of multiple DNA repair pathways by sub-nuclear damage induction methods

Christoffel Dinant; Martijn de Jager; Jeroen Essers; Wiggert A. van Cappellen; Roland Kanaar; Adriaan B. Houtsmuller; Wim Vermeulen

Live cell studies of DNA repair mechanisms are greatly enhanced by new developments in real-time visualization of repair factors in living cells. Combined with recent advances in local sub-nuclear DNA damage induction procedures these methods have yielded detailed information on the dynamics of damage recognition and repair. Here we analyze and discuss the various types of DNA damage induced in cells by three different local damage induction methods: pulsed 800 nm laser irradiation, Hoechst 33342 treatment combined with 405 nm laser irradiation and UV-C (266 nm) laser irradiation. A wide variety of damage was detected with the first two methods, including pyrimidine dimers and single- and double-strand breaks. However, many aspects of the cellular response to presensitization by Hoechst 33342 and subsequent 405 nm irradiation were aberrant from those to every other DNA damaging method described here or in the literature. Whereas, application of low-dose 266 nm laser irradiation induced only UV-specific DNA photo-lesions allowing the study of the UV-C-induced DNA damage response in a user-defined area in cultured cells.


Epigenetics & Chromatin | 2008

Chromatin structure and DNA damage repair

Christoffel Dinant; Adriaan B. Houtsmuller; Wim Vermeulen

The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. These damaging agents can induce a wide variety of lesions in the DNA, such as double strand breaks, single strand breaks, oxidative lesions and pyrimidine dimers. The cell has evolved intricate DNA damage response mechanisms to counteract the genotoxic effects of these lesions. The two main features of the DNA damage response mechanisms are cell-cycle checkpoint activation and, at the heart of the response, DNA repair. For both damage signalling and repair, chromatin remodelling is most likely a prerequisite. Here, we discuss current knowledge on chromatin remodelling with respect to the cellular response to DNA damage, with emphasis on the response to lesions resolved by nucleotide excision repair. We will discuss the role of histone modifications as well as their displacement or exchange in nucleotide excision repair and make a comparison with their requirement in transcription and double strand break repair.


Molecular and Cellular Biology | 2009

The Emerging Role of HP1 in the DNA Damage Response

Christoffel Dinant; Martijn S. Luijsterburg

ABSTRACT Heterochromatin protein 1 (HP1) family members are versatile proteins involved in transcription, chromatin organization, and replication. Recent findings now have implicated HP1 proteins in the DNA damage response as well. Cell-biological approaches showed that reducing the levels of all three HP1 isoforms enhances DNA repair, possibly due to heterochromatin relaxation. Additionally, HP1 is phosphorylated in response to DNA damage, which was suggested to initiate the DNA damage response. These findings have led to the conclusion that heterochromatic proteins are inhibitory to repair and that their dissociation from heterochromatin may facilitate repair. In contrast with an inhibitory role, a more active role for HP1 in DNA repair also was proposed based on the finding that all HP1 isoforms are recruited to UV-induced lesions, oxidative lesions, and DNA breaks. The loss of HP1 renders nematodes highly sensitive to DNA damage, and mice lacking HP1β suffer from genomic instability, suggesting that the loss of HP1 is not necessarily beneficial for repair. These findings raise the possibility that HP1 facilitates DNA repair by reorganizing chromatin, which may involve interactions between phosphorylated HP1 and other DNA damage response proteins. Taken together, these studies illustrate an emerging role of HP1 proteins in the response to genotoxic stress.


Journal of Cell Science | 2008

Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC

Deborah Hoogstraten; Steven Bergink; Jessica M.Y. Ng; Vincent Verbiest; Martijn S. Luijsterburg; Bart Geverts; Anja Raams; Christoffel Dinant; Jan H.J. Hoeijmakers; Wim Vermeulen; Adriaan B. Houtsmuller

To investigate how the nucleotide excision repair initiator XPC locates DNA damage in mammalian cell nuclei we analyzed the dynamics of GFP-tagged XPC. Photobleaching experiments showed that XPC constantly associates with and dissociates from chromatin in the absence of DNA damage. DNA-damaging agents retard the mobility of XPC, and UV damage has the most pronounced effect on the mobility of XPC-GFP. XPC exhibited a surprising distinct dynamic behavior and subnuclear distribution compared with other NER factors. Moreover, we uncovered a novel regulatory mechanism for XPC. Under unchallenged conditions, XPC is continuously exported from and imported into the nucleus, which is impeded when NER lesions are present. XPC is omnipresent in the nucleus, allowing a quick response to genotoxic stress. To avoid excessive DNA probing by the low specificity of the protein, the steady-state level in the nucleus is controlled by nucleus-cytoplasm shuttling, allowing temporally higher concentrations of XPC in the nucleus under genotoxic stress conditions.


Molecular Cell | 2013

Enhanced Chromatin Dynamics by FACT Promotes Transcriptional Restart after UV-Induced DNA Damage

Christoffel Dinant; Giannis Ampatziadis-Michailidis; Hannes Lans; Maria Tresini; Anna Lagarou; Małgorzata Grosbart; Arjan F. Theil; Wiggert A. van Cappellen; Hiroshi Kimura; Jiri Bartek; Maria Fousteri; Adriaan B. Houtsmuller; Wim Vermeulen; Jurgen A. Marteijn

Chromatin remodeling is tightly linked to all DNA-transacting activities. To study chromatin remodeling during DNA repair, we established quantitative fluorescence imaging methods to measure the exchange of histones in chromatin in living cells. We show that particularly H2A and H2B are evicted and replaced at an accelerated pace at sites of UV-induced DNA damage. This accelerated exchange of H2A/H2B is facilitated by SPT16, one of the two subunits of the histone chaperone FACT (facilitates chromatin transcription) but largely independent of its partner SSRP1. Interestingly, SPT16 is targeted to sites of UV light-induced DNA damage-arrested transcription and is required for efficient restart of RNA synthesis upon damage removal. Together, our data uncover an important role for chromatin dynamics at the crossroads of transcription and the UV-induced DNA damage response.


PLOS Biology | 2006

Dynamic interaction of TTDA with TFIIH is stabilized by nucleotide excision repair in living cells.

Giuseppina Giglia-Mari; Catherine Miquel; Arjan F. Theil; Pierre-Olivier Mari; Deborah Hoogstraten; Jessica M.Y. Ng; Christoffel Dinant; Jan H.J. Hoeijmakers; Wim Vermeulen

Transcription/repair factor IIH (TFIIH) is essential for RNA polymerase II transcription and nucleotide excision repair (NER). This multi-subunit complex consists of ten polypeptides, including the recently identified small 8-kDa trichothiodystrophy group A (TTDA)/ hTFB5 protein. Patients belonging to the rare neurodevelopmental repair syndrome TTD-A carry inactivating mutations in the TTDA/hTFB5 gene. One of these mutations completely inactivates the protein, whereas other TFIIH genes only tolerate point mutations that do not compromise the essential role in transcription. Nevertheless, the severe NER-deficiency in TTD-A suggests that the TTDA protein is critical for repair. Using a fluorescently tagged and biologically active version of TTDA, we have investigated the involvement of TTDA in repair and transcription in living cells. Under non-challenging conditions, TTDA is present in two distinct kinetic pools: one bound to TFIIH, and a free fraction that shuttles between the cytoplasm and nucleus. After induction of NER-specific DNA lesions, the equilibrium between these two pools dramatically shifts towards a more stable association of TTDA to TFIIH. Modulating transcriptional activity in cells did not induce a similar shift in this equilibrium. Surprisingly, DNA conformations that only provoke an abortive-type of NER reaction do not result into a more stable incorporation of TTDA into TFIIH. These findings identify TTDA as the first TFIIH subunit with a primarily NER-dedicated role in vivo and indicate that its interaction with TFIIH reflects productive NER.


Journal of Cell Biology | 2009

Human Fbh1 helicase contributes to genome maintenance via pro- and anti-recombinase activities

Kasper Fugger; Martin Mistrik; Jannie Rendtlew Danielsen; Christoffel Dinant; Jacob Falck; Jiri Bartek; Jiri Lukas; Niels Mailand

Human Fbh1 helicase contributes to genome maintenance via pro- and anti-recombinase activities.

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Wim Vermeulen

Erasmus University Rotterdam

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Jan H.J. Hoeijmakers

Erasmus University Rotterdam

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Martijn S. Luijsterburg

Leiden University Medical Center

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Deborah Hoogstraten

Erasmus University Rotterdam

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Jessica M.Y. Ng

Erasmus University Rotterdam

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Steven Bergink

Erasmus University Rotterdam

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Vincent Verbiest

Erasmus University Rotterdam

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Jiri Lukas

University of Copenhagen

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Anja Raams

Erasmus University Rotterdam

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