Uv Induced (6‐4) Photoproducts Are Distributed Differently Than Cyclobutane Dimers in Nucleosomes

Gale, James M.; Smerdon, Michael J.

doi:10.1111/j.1751-1097.1990.tb01732.x

Cited by 94 publications

(64 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1) (28). Also, CPDs tend to form away from the histone surface in UV-irradiated nucleosomes, chromatin, or intact human cells (23,25,39). Surprisingly, in this study we found that CTDs can adapt to different rotational settings as dictated by the TG motif (Figs.…”

Section: Discussionmentioning

confidence: 43%

“…However, CPDs do not displace DNA from histones, and nucleosomes containing CPDs can be readily isolated or prepared (23,24). Furthermore, DNA interactions within nucleosomes do not significantly affect the overall frequency of CPD formation, because there is only an ϳ1.5-fold difference in CPD yield between linker DNA and DNA bound to nucleosomes (25,26). Rather, DNA interactions within nucleosomes affect the site of the lesion (23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Accommodation and Repair of a UV Photoproduct in DNA at Different Rotational Settings on the Nucleosome Surface

Svedružić

Wang²,

Kosmoski³

et al. 2005

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Cyclobutane-thymine dimers (CTDs), the most common DNA lesion induced by UV radiation, cause 30°bending and 9°unwinding of the DNA helix. We prepared site-specific CTDs within a short sequence bracketed by strong nucleosome-positioning sequences. The rotational setting of CTDs over one turn of the helix near the dyad center on the histone surface was analyzed by hydroxyl radical footprinting. Surprisingly, the position of CTDs over one turn of the helix does not affect the rotational setting of DNA on the nucleosome surface. Gel-shift analysis indicates that one CTD destabilizes histone-DNA interactions by 0.6 or 1.1 kJ/mol when facing away or toward the histone surface, respectively. Thus, 0.5 kJ/mol energy penalty for a buried CTD is not enough to change the rotational setting of sequences with strong rotational preference. The effect of rotational setting on CTD removal by nucleotide excision repair (NER) was examined using Xenopus oocyte nuclear extracts. The NER rates are only 2-3 times lower in nucleosomes and change by only 1.5-fold when CTDs face away or toward the histone surface. Therefore, in Xenopus nuclear extracts, the rotational orientation of CTDs on nucleosomes has surprisingly little effect on rates of repair. These results indicate that nucleosome dynamics and/or chromatin remodeling may facilitate NER in gaining access to DNA damage in nucleosomes.In eukaryotes, DNA is organized in chromatin structures within the cell nucleus. The chromatin serves a dual purpose, tight DNA packing within the nucleus and organization of dynamic processes such as DNA transcription, replication, and repair. Of these, DNA repair protects genomic integrity from DNA-damaging agents and is vital for cell survival (1). Indeed, occasional failures in DNA repair can lead to aging and to multiple diseases, including cancer (2, 3). When DNA is irradiated with UV light, adjacent pyrimidines can form stable covalent bonds, yielding cis-syn cyclobutane-pyrimidine dimers (CPDs).5 A common UV lesion caused by exposure to direct sunlight, CPDs can lead to skin cancer, one of the most common forms of cancer (4). The CPD lesion can stall DNA replication (5) and transcription (6) and disrupt DNA interactions with other proteins that regulate gene expression (6). Each of these events can lead to genetic instability.The effect of chromatin structure on repair of UV damage was first implicated by the findings of Wilkins and Hart (7). These authors showed that UV-induced lesions in permeable human cells are removed more slowly from DNA that is less accessible to lesion-specific nucleases in chromatin. It was then found that newly repaired DNA in UVirradiated human fibroblasts is initially more accessible to exogenous nucleases than bulk DNA in chromatin (8) and that nucleosome rearrangement occurs in these regions (9). Studies with a yeast mini-chromosome showed that repair of CPDs is faster in nucleosome-free segments of DNA, being highest in the transcribed strand of a selectable gene and correlating with transcription rate in diff...

show abstract

Section: Discussionmentioning

confidence: 43%

mentioning

confidence: 99%

Accommodation and Repair of a UV Photoproduct in DNA at Different Rotational Settings on the Nucleosome Surface

Svedružić

Wang²,

Kosmoski³

et al. 2005

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The difference between the repair efficiencies for these lesions probably reflects the fact the (6-4)PPs are a better substrate for NER than are CPDs (10), most likely because they cause a greater distortion of the double helix structure, but also because of their preferential locations in the linker regions of nucleosomes (11). This is reminiscent of our previous observations in fetal human neurons, which, when kept in culture for several months, lost the ability to efficiently repair CPDs, but still dealt efficiently with (6-4)PPs (1).…”

Section: Ner Is Impaired At the Global Genomic Level Upon Macrophagementioning

confidence: 99%

Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme

Nouspikel

Hanawalt

2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Global nucleotide excision repair is greatly attenuated in terminally differentiated mammalian cells. We observed this phenomenon in human neurons and in macrophages, noting that the transcriptioncoupled repair pathway remains functional and that there is no significant reduction in levels of excision repair enzymes. We have discovered that ubiquitin-activating enzyme E1 complements the repair deficiency in macrophage extracts, and although there is no reduction in the concentration of E1 upon differentiation, our results indicate a reduction in phosphorylation of E1. In preliminary studies, we have identified the basal transcription factor TFIIH as the potential target for ubiquitination. We suggest that this unusual type of regulation at the level of the E1 enzyme is likely to affect numerous cellular processes and may represent a strategy to coordinate multiple phenotypic changes upon differentiation by using E1 as a ''master switch.'' DNA repair ͉ TFIIH ͉ ubiquitination ͉ monocytes ͉ differentiated N ucleotide excision repair (NER) is the most versatile DNA repair system; it handles a wide variety of lesions, from UV-induced pyrimidine dimers to bulky chemical adducts, to intrastrand DNA cross-links and even bound protein fragments. The early steps in NER can be divided into two subpathways: global genomic repair (GGR) that recognizes and removes lesions throughout the genome, and transcription-coupled repair (TCR) that preferentially repairs the transcribed strand of active genes, most likely by using translocating RNA polymerase as a lesion sensor.The efficiency of NER is known to be affected by cellular differentiation (reviewed in ref. 1). In particular the GGR subpathway is greatly attenuated in human neurons, either primary (1) or derived from NT2 neuroteratoma cells (2), whereas TCR is still active in both cases. In the terminally differentiated cells, however, the nontranscribed strand in active genes is also efficiently repaired, a phenomenon that we have termed differentiation-associated repair (DAR) and which we have reasoned is required to maintain lesion-free templates for TCR.It seems likely that attenuation of NER at the global genome level, and its reliance on TCR and DAR to maintain the essential active genes, is common in terminally differentiated cells. Indeed, studies with other differentiated cell systems have yielded similar results. Among numerous examples, rat skeletal myocytes exhibited a decrease in repair synthesis in the course of differentiation (3, 4), whereas TCR was less affected (4). Mouse 3T3 cells displayed attenuated UV-induced repair synthesis after differentiation into adipocytes (5). The repair of UV-induced lesions was reduced in differentiated keratinocytes, compared with that in cells from the basal layers of human skin (6). Human neuroblastomas repaired benzo[a]pyrene diol-epoxide adducts less rapidly after differentiation (7), and differentiated mouse neuroblastomas exhibited similar deficiencies in the repair of UV-induced lesions (8).What is the mechanism by whic...

show abstract

“…On the one hand, packaging can protect DNA from damaging agents (22,23). On the other hand, it can hinder damage recognition and the access of repair machinery.…”

Section: Regions Repaired Later Are Associated With Higher Mutagenesismentioning

confidence: 99%

Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis

Adar

Lieb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

226

View full text Add to dashboard Cite

We recently developed a high-resolution genome-wide assay for mapping DNA excision repair named eXcision Repair-sequencing (XR-seq) and have now used XR-seq to determine which regions of the genome are subject to repair very soon after UV exposure and which regions are repaired later. Over a time course, we measured repair of the UV-induced damage of cyclobutane pyrimidine dimers (CPDs) (at 1, 4, 8, 16, 24, and 48 h) and (6-4)pyrimidinepyrimidone photoproducts [(6-4)PPs] (at 5 and 20 min and 1, 2, and 4 h) in normal human skin fibroblasts. Each type of damage has distinct repair kinetics. The (6-4)PPs are detected as early as 5 min after UV treatment, with the bulk of repair completed by 4 h. Repair of CPDs, which we previously showed is intimately coupled to transcription, is slower and in certain regions persists even 2 d after UV irradiation. We compared our results to the Encyclopedia of DNA Elements data regarding histone modifications, chromatin state, and transcription. For both damage types, and for both transcription-coupled and general excision repair, the earliest repair occurred preferentially in active and open chromatin states. Conversely, repair in regions classified as "heterochromatic" and "repressed" was relatively low at early time points, with repair persisting into the late time points. Damage that remains during DNA replication increases the risk for mutagenesis. Indeed, laterepaired regions are associated with a higher level of cancer-linked mutations. In summary, we show that XR-seq is a powerful approach for studying relationships among chromatin state, DNA repair, genome stability, mutagenesis, and carcinogenesis.DNA repair | DNA damage | chromatin | transcription | mutation D NA damage blocks transcription and replication and compromises the integrity of the genome. Bulky adducts in DNA, the focus of this work, are caused by a variety of genotoxic agents including UV radiation in sunlight. In human cells, this damage is removed exclusively by the nucleotide excision repair mechanism (1-3). In nucleotide excision repair, a single-stranded oligomer that contains the bulky adduct is excised by dual incisions bracketing the lesion. The resulting gap is filled in by DNA polymerases, and the newly synthesized repair patch is then sealed by DNA ligase. In general excision repair, damage recognition is achieved by the repair factors xeroderma pigmentosum (XP) complementation group C (XPC) together with replication protein A (RPA) and XPA (4-6). In DNA that is being actively transcribed, damage recognition can also be achieved by a stalled RNA polymerase II, which, with the aid of the Cockayne Syndrome B (CSB) protein, accelerates the recruitment of the excision repair factors. This recognition process leads to transcription-coupled repair (7,8). The subsequent dual-incision reaction is carried out by the core excision repair factors RPA, XPA, transcription factor II H (TFIIH), XPG, and XPF-ERCC1, releasing an excised oligomer that is 24-32 nucleotides (nt) in length (6, 9).The mechanism of DNA...

show abstract

Uv Induced (6‐4) Photoproducts Are Distributed Differently Than Cyclobutane Dimers in Nucleosomes

Cited by 94 publications

References 38 publications

Accommodation and Repair of a UV Photoproduct in DNA at Different Rotational Settings on the Nucleosome Surface

Accommodation and Repair of a UV Photoproduct in DNA at Different Rotational Settings on the Nucleosome Surface

Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme

Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis

Contact Info

Product

Resources

About