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Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans
Joel N Meyer, Windy A Boyd, Gregory A Azzam, Astrid C Haugen, Jonathan H Freedman, Bennett Van Houten
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-5-r70
Abstract: UVC radiation induced lesions in young adult C. elegans, with a slope of 0.4 to 0.5 lesions per 10 kilobases of DNA per 100 J/m2, in both nuclear and mitochondrial targets. L1 and dauer larvae were more than fivefold more sensitive to lesion formation than were young adults. Nuclear repair kinetics in a well expressed nuclear gene were biphasic in nongravid adult nematodes: a faster, first order (half-life about 16 hours) phase lasting approximately 24 hours and resulting in removal of about 60% of the photoproducts was followed by a much slower phase. Repair in ten nuclear DNA regions was 15% and 50% higher in more actively transcribed regions in young and aging adults, respectively. Finally, repair was reduced by 30% to 50% in each of the ten nuclear regions in aging adults. However, this decrease in repair could not be explained by a reduction in expression of nucleotide excision repair genes, and we present a plausible mechanism, based on gene expression data, to account for this decrease.Repair of UVC-induced DNA damage in C. elegans is similar kinetically and genetically to repair in humans. Furthermore, this important repair process slows significantly in aging C. elegans, the first whole organism in which this question has been addressed.In vitro assays, cell culture systems, and simple unicellular organisms continue to be crucial in elucidating mechanistic aspects of the formation and repair of DNA damage. However, the ability to study DNA damage, and especially its repair in vivo, is somewhat limited in metazoans. Studies in mouse models have been very informative, but they are also expensive and time consuming. Caenorhabditis elegans is a powerful system that is increasingly used to study many human conditions that are affected by DNA damage and repair, including carcinogenesis [1,2], neurodegenerative diseases [3,4], and aging [5,6]. Homologs of many human DNA genes are present in the C. elegans genome [7,8], suggesting that this simple multicellular euk
Inhibition of nucleotide excision repair by arsenic
Shengwen Shen,Chuan Wang,Michael Weinfeld,X. Chris Le
Chinese Science Bulletin , 2013, DOI: 10.1007/s11434-012-5439-x
Abstract: Inhibition of DNA repair is one proposed mechanism for the co-mutagenicity/co-carcinogenicity of arsenic. This review summarizes the current literature on the effects of arsenic compounds on nucleotide excision repair (NER). Several possible mechanisms for the observed NER inhibition have been proposed. Modulation of the expression of NER proteins has been considered to be one possibility of impairing the NER process. However, data on the effects of arsenic on the expression of NER proteins remain inconsistent. It is more likely that arsenic inhibits the induction of accessory or other key proteins involved in cellular control of DNA repair pathways, such as p53. For example, arsenic affects p53 phosphorylation and p53 DNA binding activity, which could regulate NER through transcriptional activation of downstream NER genes. Although it is important to study possible direct inactivation of NER proteins by arsenic binding, indirect inactivation of proteins having thiol residues critical to their function or zinc finger proteins cannot be negated. For example, nitric oxide (NO) induced in arsenic-treated cells serves as a specific inhibitor of NER, possibly through NO-induced S-nitrosylation of proteins related to DNA repair. Poly(ADP-ribose) polymerase-1, a zinc finger protein implicated in both NER and base excision repair (BER), deserves special attention because of its involvement in NO production and its broad range of protein substrates including many repair enzymes.
SLX-1 Is Required for Maintaining Genomic Integrity and Promoting Meiotic Noncrossovers in the Caenorhabditis elegans Germline  [PDF]
Takamune T. Saito equal contributor,Firaz Mohideen equal contributor,Katherine Meyer,J. Wade Harper,Monica P. Colaiácovo
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002888
Abstract: Although the SLX4 complex, which includes structure-specific nucleases such as XPF, MUS81, and SLX1, plays important roles in the repair of several kinds of DNA damage, the function of SLX1 in the germline remains unknown. Here we characterized the endonuclease activities of the Caenorhabditis elegans SLX-1-HIM-18/SLX-4 complex co-purified from human 293T cells and determined SLX-1 germline function via analysis of slx-1(tm2644) mutants. SLX-1 shows a HIM-18/SLX-4–dependent endonuclease activity toward replication forks, 5′-flaps, and Holliday junctions. slx-1 mutants exhibit hypersensitivity to UV, nitrogen mustard, and camptothecin, but not gamma irradiation. Consistent with a role in DNA repair, recombination intermediates accumulate in both mitotic and meiotic germ cells in slx-1 mutants. Importantly, meiotic crossover distribution, but not crossover frequency, is altered on chromosomes in slx-1 mutants compared to wild type. This alteration is not due to changes in either the levels or distribution of double-strand breaks (DSBs) along chromosomes. We propose that SLX-1 is required for repair at stalled or collapsed replication forks, interstrand crosslink repair, and nucleotide excision repair during mitosis. Moreover, we hypothesize that SLX-1 regulates the crossover landscape during meiosis by acting as a noncrossover-promoting factor in a subset of DSBs.
Histone Displacement during Nucleotide Excision Repair  [PDF]
Christoffel Dinant,Jiri Bartek,Simon Bekker-Jensen
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms131013322
Abstract: Nucleotide excision repair (NER) is an important DNA repair mechanism required for cellular resistance against UV light and toxic chemicals such as those found in tobacco smoke. In living cells, NER efficiently detects and removes DNA lesions within the large nuclear macromolecular complex called chromatin. The condensed nature of chromatin inhibits many DNA metabolizing activities, including NER. In order to promote efficient repair, detection of a lesion not only has to activate the NER pathway but also chromatin remodeling. In general, such remodeling is thought on the one hand to precede NER, thus allowing repair proteins to efficiently access DNA. On the other hand, after completion of the repair, the chromatin must be returned to its previous undamaged state. Chromatin remodeling can refer to three separate but interconnected processes, histone post-translational modifications, insertion of histone variants and histone displacement (including nucleosome sliding). Here we review current knowledge, and speculate about current unknowns, regarding those chromatin remodeling activities that physically displace histones before, during and after NER.
Base Sequence Context Effects on Nucleotide Excision Repair  [PDF]
Yuqin Cai,Dinshaw J. Patel,Suse Broyde,Nicholas E. Geacintov
Journal of Nucleic Acids , 2010, DOI: 10.4061/2010/174252
Abstract: Nucleotide excision repair (NER) plays a critical role in maintaining the integrity of the genome when damaged by bulky DNA lesions, since inefficient repair can cause mutations and human diseases notably cancer. The structural properties of DNA lesions that determine their relative susceptibilities to NER are therefore of great interest. As a model system, we have investigated the major mutagenic lesion derived from the environmental carcinogen benzo[a]pyrene (B[a]P), 10S (+)-trans-anti-B[a]P- -dG in six different sequence contexts that differ in how the lesion is positioned in relation to nearby guanine amino groups. We have obtained molecular structural data by NMR and MD simulations, bending properties from gel electrophoresis studies, and NER data obtained from human HeLa cell extracts for our six investigated sequence contexts. This model system suggests that disturbed Watson-Crick base pairing is a better recognition signal than a flexible bend, and that these can act in concert to provide an enhanced signal. Steric hinderance between the minor groove-aligned lesion and nearby guanine amino groups determines the exact nature of the disturbances. Both nearest neighbor and more distant neighbor sequence contexts have an impact. Regardless of the exact distortions, we hypothesize that they provide a local thermodynamic destabilization signal for repair. 1. Introduction Nucleotide excision repair (NER) plays a central role in preserving the genome of prokaryotes and eukaryotes. This versatile repair system removes structurally and chemically diverse bulky DNA lesions, including those induced by exposure to UV light and environmental chemical carcinogens [1, 2]. The vital importance of this mechanism is demonstrated by several human NER-deficiency syndromes including xeroderma pigmentosum (XP), cockayne syndrome (CS), and trichothiodystrophy (TTD) [3]. XP, for example, is characterized by high photosensitivity, hyperpigmentation, premature skin ageing, and proneness to developing skin cancer [4]. Furthermore, the capacity of the NER pathway is important in cancer chemotherapy [5]: NER diminishes the efficacy of chemotherapeutic agents such as cisplatin, which act via the formation of bulky DNA adducts. A better understanding of the mechanisms of recognition of DNA lesions by the NER system may lead to the design of improved chemotherapeutic drugs that can modulate the repair response. Recent findings reveal that polymorphisms in human NER repair genes have an impact on the repair of DNA lesions and cancer susceptibility [6, 7], as well as on
Implication of Posttranslational Histone Modifications in Nucleotide Excision Repair  [PDF]
Shisheng Li
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms131012461
Abstract: Histones are highly alkaline proteins that package and order the DNA into chromatin in eukaryotic cells. Nucleotide excision repair (NER) is a conserved multistep reaction that removes a wide range of generally bulky and/or helix-distorting DNA lesions. Although the core biochemical mechanism of NER is relatively well known, how cells detect and repair lesions in diverse chromatin environments is still under intensive research. As with all DNA-related processes, the NER machinery must deal with the presence of organized chromatin and the physical obstacles it presents. A huge catalogue of posttranslational histone modifications has been documented. Although a comprehensive understanding of most of these modifications is still lacking, they are believed to be important regulatory elements for many biological processes, including DNA replication and repair, transcription and cell cycle control. Some of these modifications, including acetylation, methylation, phosphorylation and ubiquitination on the four core histones (H2A, H2B, H3 and H4) or the histone H2A variant H2AX, have been found to be implicated in different stages of the NER process. This review will summarize our recent understanding in this area.
Involvement of Global Genome Repair, Transcription Coupled Repair, and Chromatin Remodeling in UV DNA Damage Response Changes during Development  [PDF]
Hannes Lans ,Jurgen A. Marteijn,Bj?rn Schumacher,Jan H. J. Hoeijmakers,Gert Jansen,Wim Vermeulen
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000941
Abstract: Nucleotide Excision Repair (NER), which removes a variety of helix-distorting lesions from DNA, is initiated by two distinct DNA damage-sensing mechanisms. Transcription Coupled Repair (TCR) removes damage from the active strand of transcribed genes and depends on the SWI/SNF family protein CSB. Global Genome Repair (GGR) removes damage present elsewhere in the genome and depends on damage recognition by the XPC/RAD23/Centrin2 complex. Currently, it is not well understood to what extent both pathways contribute to genome maintenance and cell survival in a developing organism exposed to UV light. Here, we show that eukaryotic NER, initiated by two distinct subpathways, is well conserved in the nematode Caenorhabditis elegans. In C. elegans, involvement of TCR and GGR in the UV-induced DNA damage response changes during development. In germ cells and early embryos, we find that GGR is the major pathway contributing to normal development and survival after UV irradiation, whereas in later developmental stages TCR is predominantly engaged. Furthermore, we identify four ISWI/Cohesin and four SWI/SNF family chromatin remodeling factors that are implicated in the UV damage response in a developmental stage dependent manner. These in vivo studies strongly suggest that involvement of different repair pathways and chromatin remodeling proteins in UV-induced DNA repair depends on developmental stage of cells.
Disruption of TTDA Results in Complete Nucleotide Excision Repair Deficiency and Embryonic Lethality  [PDF]
Arjan F. Theil,Julie Nonnekens,Barbara Steurer,Pierre-Olivier Mari,Jan de Wit,Charlène Lemaitre,Jurgen A. Marteijn,Anja Raams,Alex Maas,Marcel Vermeij,Jeroen Essers,Jan H. J. Hoeijmakers,Giuseppina Giglia-Mari ,Wim Vermeulen
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003431
Abstract: The ten-subunit transcription factor IIH (TFIIH) plays a crucial role in transcription and nucleotide excision repair (NER). Inactivating mutations in the smallest 8-kDa TFB5/TTDA subunit cause the neurodevelopmental progeroid repair syndrome trichothiodystrophy A (TTD-A). Previous studies have shown that TTDA is the only TFIIH subunit that appears not to be essential for NER, transcription, or viability. We studied the consequences of TTDA inactivation by generating a Ttda knock-out (Ttda?/?) mouse-model resembling TTD-A patients. Unexpectedly, Ttda?/? mice were embryonic lethal. However, in contrast to full disruption of all other TFIIH subunits, viability of Ttda?/? cells was not affected. Surprisingly, Ttda?/? cells were completely NER deficient, contrary to the incomplete NER deficiency of TTD-A patient-derived cells. We further showed that TTD-A patient mutations only partially inactivate TTDA function, explaining the relatively mild repair phenotype of TTD-A cells. Moreover, Ttda?/? cells were also highly sensitive to oxidizing agents. These findings reveal an essential role of TTDA for life, nucleotide excision repair, and oxidative DNA damage repair and identify Ttda?/? cells as a unique class of TFIIH mutants.
Chromatin Dynamics during Nucleotide Excision Repair: Histones on the Move  [PDF]
Salomé Adam,Sophie E. Polo
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms130911895
Abstract: It has been a long-standing question how DNA damage repair proceeds in a nuclear environment where DNA is packaged into chromatin. Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair. Here, we review the methods that have been developed over the years to delineate chromatin alterations in response to DNA damage by focusing on the well-characterized Nucleotide Excision Repair (NER) pathway. We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity. In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair.
Photoreactive DNA as a tool for studying topography of nucleotide excision repair complex
Rechkunova N. I.,Krasikova Y. S.,Maltseva E. A.,Lavrik O. I.
Biopolymers and Cell , 2012,
Abstract: Nucleotide excision repair (NER) is one of the major DNA repair pathways in eukaryotic cells preventing genetic abnormalities caused by DNA damage. NER removes a wide set of structurally diverse lesions such as pyrimidine dimers arising upon UV irradiation and bulky chemical adducts arising upon exposure to environmental carcinogens or chemotherapeutic drugs. In view of the extraordinarily broad substrate specificity of NER, it is of interest to understand how a certain set of proteins recognizes various DNA lesions in the context of a large excess of intact DNA. This review focuses on contribution of photoaffinity labeling technique in the study of DNA damage recognition and following stages resulting in preincision complex assembly, the key and still most unclear steps of NER.
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