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Article ; Online: Multi-scale cellular imaging of DNA double strand break repair.

Heemskerk, Tim / van de Kamp, Gerarda / Essers, Jeroen / Kanaar, Roland / Paul, Maarten W

2023 Volume 131, Page(s) 103570

Abstract: Live-cell and high-resolution fluorescence microscopy are powerful tools to study the organization and dynamics of DNA double-strand break repair foci and specific repair proteins in single cells. This requires specific induction of DNA double-strand ... ...

Abstract	Live-cell and high-resolution fluorescence microscopy are powerful tools to study the organization and dynamics of DNA double-strand break repair foci and specific repair proteins in single cells. This requires specific induction of DNA double-strand breaks and fluorescent markers to follow the DNA lesions in living cells. In this review, where we focused on mammalian cell studies, we discuss different methods to induce DNA double-strand breaks, how to visualize and quantify repair foci in living cells., We describe different (live-cell) imaging modalities that can reveal details of the DNA double-strand break repair process across multiple time and spatial scales. In addition, recent developments are discussed in super-resolution imaging and single-molecule tracking, and how these technologies can be applied to elucidate details on structural compositions or dynamics of DNA double-strand break repair.
MeSH term(s)	Animals ; DNA Repair ; DNA Breaks, Double-Stranded ; Microscopy, Fluorescence/methods ; Single Molecule Imaging ; DNA ; Mammals/genetics
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2023-09-19
Publishing country	Netherlands
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2023.103570
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Article: DNA Double Strand Break Repair Pathways in Response to Different Types of Ionizing Radiation.

van de Kamp, Gerarda / Heemskerk, Tim / Kanaar, Roland / Essers, Jeroen

Frontiers in genetics

2021 Volume 12, Page(s) 738230

Abstract: The superior dose distribution of particle radiation compared to photon radiation makes it a promising therapy for the treatment of tumors. However, the cellular responses to particle therapy and especially the DNA damage response (DDR) is not well ... ...

Abstract	The superior dose distribution of particle radiation compared to photon radiation makes it a promising therapy for the treatment of tumors. However, the cellular responses to particle therapy and especially the DNA damage response (DDR) is not well characterized. Compared to photons, particles are thought to induce more closely spaced DNA lesions instead of isolated lesions. How this different spatial configuration of the DNA damage directs DNA repair pathway usage, is subject of current investigations. In this review, we describe recent insights into induction of DNA damage by particle radiation and how this shapes DNA end processing and subsequent DNA repair mechanisms. Additionally, we give an overview of promising DDR targets to improve particle therapy.
Language	English
Publishing date	2021-09-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.738230
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Article: DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage.

Reuvers, Thom G A / Kanaar, Roland / Nonnekens, Julie

Cancers

2020 Volume 12, Issue 8

Abstract: DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy- ... ...

Abstract	DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.
Language	English
Publishing date	2020-07-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12082098
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Article ; Online: Experimental Evidence for Enhanced Receptor Binding by Rapidly Spreading SARS-CoV-2 Variants.

Laffeber, Charlie / de Koning, Kelly / Kanaar, Roland / Lebbink, Joyce H G

Journal of molecular biology

2021 Volume 433, Issue 15, Page(s) 167058

Abstract: Rapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, ... ...

Abstract	Rapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 7-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation only slightly enhances the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 2-fold weaker than N501Y. However, the recently emerging double mutant E484K/N501Y binds even stronger than N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.
MeSH term(s)	Amino Acid Substitution ; Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Binding Sites ; HEK293 Cells ; Humans ; Hydrogen Bonding ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Domains ; SARS-CoV-2/classification ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-05-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2021.167058
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Article: Modulating the Heat Stress Response to Improve Hyperthermia-Based Anticancer Treatments.

Scutigliani, Enzo M / Liang, Yongxin / Crezee, Hans / Kanaar, Roland / Krawczyk, Przemek M

Cancers

2021 Volume 13, Issue 6

Abstract: Cancer treatments based on mild hyperthermia (39-43 °C, HT) are applied to a widening range of cancer types, but several factors limit their efficacy and slow down more widespread adoption. These factors include difficulties in adequate heat delivery, a ... ...

Abstract	Cancer treatments based on mild hyperthermia (39-43 °C, HT) are applied to a widening range of cancer types, but several factors limit their efficacy and slow down more widespread adoption. These factors include difficulties in adequate heat delivery, a short therapeutic window and the acquisition of thermotolerance by cancer cells. Here, we explore the biological effects of HT, the cellular responses to these effects and their clinically-relevant consequences. We then identify the heat stress response-the cellular defense mechanism that detects and counteracts the effects of heat-as one of the major forces limiting the efficacy of HT-based therapies and propose targeting this mechanism as a potentially universal strategy for improving their efficacy.
Language	English
Publishing date	2021-03-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13061243
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Article ; Online: Microscopy-based single-cell proteomic profiling reveals heterogeneity in DNA damage response dynamics.

Su, Pin-Rui / You, Li / Beerens, Cecile / Bezstarosti, Karel / Demmers, Jeroen / Pabst, Martin / Kanaar, Roland / Hsu, Cheng-Chih / Chien, Miao-Ping

Cell reports methods

2022 Volume 2, Issue 6, Page(s) 100237

Abstract: Single-cell proteomics has the potential to decipher tumor heterogeneity, and a method like single-cell proteomics by mass spectrometry (SCoPE-MS) allows profiling several tens of single cells for >1,000 proteins per cell. This method, however, cannot ... ...

Abstract	Single-cell proteomics has the potential to decipher tumor heterogeneity, and a method like single-cell proteomics by mass spectrometry (SCoPE-MS) allows profiling several tens of single cells for >1,000 proteins per cell. This method, however, cannot link the proteome of individual cells with phenotypes of interest. Here, we developed a microscopy-based functional single-cell proteomic-profiling technology, called FUNpro, to address this. FUNpro enables screening, identification, and isolation of single cells of interest in a real-time fashion, even if the phenotypes are dynamic or the cells of interest are rare. We applied FUNpro to proteomically profile a newly identified small subpopulation of U2OS osteosarcoma cells displaying an abnormal, prolonged DNA damage response (DDR) after ionizing radiation (IR). With this, we identified the PDS5A protein contributing to the abnormal DDR dynamics and helping the cells survive after IR.
MeSH term(s)	DNA Damage ; Microscopy ; Proteomics/methods ; Cell Cycle Proteins ; Radiation, Ionizing
Chemical Substances	Cell Cycle Proteins
Language	English
Publishing date	2022-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2667-2375
ISSN (online)	2667-2375
DOI	10.1016/j.crmeth.2022.100237
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Article: Functional Homologous Recombination (HR) Screening Shows the Majority of

Meijer, Titia G / Martens, John W M / Prager-van der Smissen, Wendy J C / Verkaik, Nicole S / Beaufort, Corine M / van Herk, Stanley / Robert-Finestra, Teresa / Hoogenboezem, Remco M / Ruigrok-Ritstier, Kirsten / Paul, Maarten W / Gribnau, Joost / Bindels, Eric M J / Kanaar, Roland / Jager, Agnes / van Gent, Dik C / Hollestelle, Antoinette

Cancers

2024 Volume 16, Issue 4

Abstract: Tumors with a ... ...

Abstract	Tumors with a pathogenic
Language	English
Publishing date	2024-02-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16040741
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Article ; Online: Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation.

de Wagenaar, Nathalie P / van den Bersselaar, Lisa M / Odijk, Hanny J H M / Stefens, Sanne J M / Reinhardt, Dieter P / Roos-Hesselink, Jolien W / Kanaar, Roland / Verhagen, Judith M A / Brüggenwirth, Hennie T / van de Laar, Ingrid M B H / van der Pluijm, Ingrid / Essers, Jeroen

Human molecular genetics

2024

Abstract: Rationale: Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis.: Objectives! ...

Abstract	Rationale: Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis. Objectives: Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants. Methods: A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts. Results: Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0-47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0-54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines. Conclusion: Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.
Language	English
Publishing date	2024-03-27
Publishing country	England
Document type	Journal Article
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddae044
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Article ; Online: Persistent TFIIH binding to non-excised DNA damage causes cell and developmental failure.

Muniesa-Vargas, Alba / Davó-Martínez, Carlota / Ribeiro-Silva, Cristina / van der Woude, Melanie / Thijssen, Karen L / Haspels, Ben / Häckes, David / Kaynak, Ülkem U / Kanaar, Roland / Marteijn, Jurgen A / Theil, Arjan F / Kuijten, Maayke M P / Vermeulen, Wim / Lans, Hannes

Nature communications

2024 Volume 15, Issue 1, Page(s) 3490

Abstract: Congenital nucleotide excision repair (NER) deficiency gives rise to several cancer-prone and/or progeroid disorders. It is not understood how defects in the same DNA repair pathway cause different disease features and severity. Here, we show that the ... ...

Abstract	Congenital nucleotide excision repair (NER) deficiency gives rise to several cancer-prone and/or progeroid disorders. It is not understood how defects in the same DNA repair pathway cause different disease features and severity. Here, we show that the absence of functional ERCC1-XPF or XPG endonucleases leads to stable and prolonged binding of the transcription/DNA repair factor TFIIH to DNA damage, which correlates with disease severity and induces senescence features in human cells. In vivo, in C. elegans, this prolonged TFIIH binding to non-excised DNA damage causes developmental arrest and neuronal dysfunction, in a manner dependent on transcription-coupled NER. NER factors XPA and TTDA both promote stable TFIIH DNA binding and their depletion therefore suppresses these severe phenotypical consequences. These results identify stalled NER intermediates as pathogenic to cell functionality and organismal development, which can in part explain why mutations in XPF or XPG cause different disease features than mutations in XPA or TTDA.
MeSH term(s)	Caenorhabditis elegans/metabolism ; Caenorhabditis elegans/genetics ; DNA Damage ; Humans ; Animals ; DNA Repair ; Transcription Factor TFIIH/metabolism ; Transcription Factor TFIIH/genetics ; DNA-Binding Proteins/metabolism ; DNA-Binding Proteins/genetics ; Endonucleases/metabolism ; Endonucleases/genetics ; Caenorhabditis elegans Proteins/metabolism ; Caenorhabditis elegans Proteins/genetics ; Xeroderma Pigmentosum Group A Protein/metabolism ; Xeroderma Pigmentosum Group A Protein/genetics ; Protein Binding ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Mutation ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics
Chemical Substances	Transcription Factor TFIIH (148710-81-0) ; DNA-Binding Proteins ; Endonucleases (EC 3.1.-) ; xeroderma pigmentosum group F protein ; Caenorhabditis elegans Proteins ; Xeroderma Pigmentosum Group A Protein ; DNA excision repair protein ERCC-5 ; Transcription Factors ; ERCC1 protein, human (EC 3.1.-) ; XPA protein, human ; Nuclear Proteins
Language	English
Publishing date	2024-04-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47935-9
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Article ; Online: Experimental evidence for enhanced receptor binding by rapidly spreading SARS-CoV-2 variants

Laffeber, Charlie / de Koning, Kelly / Kanaar, Roland / Lebbink, Joyce

bioRxiv

Abstract	Rapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 9-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation does not significantly influence the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 3-fold weaker than N501Y. The recently emerging double mutant E484K/N501Y binds as tight as N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.
Keywords	covid19
Language	English
Publishing date	2021-02-22
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.02.22.432357
Database	COVID19

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