In 1989, transcription–repair coupling (TRC) was first described in Escherichia coli, as the transcription‐dependent, preferential nucleotide excision repair (NER) of UV photoproducts located in the ...template DNA strand. This finding led to pioneering biochemical studies of TRC in the laboratory of Professor Aziz Sancar, where, at the time, major contributions were being made toward understanding the roles of the UvrA, UvrB and UvrC proteins in NER. When the repair studies were extended to TRC, template but not coding strand lesions were found to block RNA polymerase (RNAP) in vitro, and unexpectedly, the blocked RNAP inhibited NER. A transcription–repair coupling factor, also called Mfd protein, was found to remove the blocked RNAP, deliver the repair enzyme to the lesion and thereby mediate more rapid repair of the transcription‐blocking lesion compared with lesions elsewhere. Structural and functional analyses of Mfd protein revealed helicase motifs responsible for ATP hydrolysis and DNA binding, and regions that interact with RNAP and UvrA. These and additional studies provided a basis upon which other investigators, in following decades, have characterized fascinating and unexpected structural and mechanistic features of Mfd, revealed the possible existence of additional pathways of TRC and discovered additional roles of Mfd in the cell.
Pivotal intermediate in transcription–repair coupling. RNA polymerase (RNAP) is tethered to DNA via Mfd protein, with DNA partially wrapped around Mfd. This structure forms after RNAP becomes blocked by a template strand lesion (here, a cyclobutane thymine dimer, TT). Mfd removes blocked RNAP and RNA from DNA. Mfd in this resulting tethered intermediate assumes a conformation that binds strongly to the UvrA–UvrB nucleotide excision repair proteins. The next step, binding to and delivering the repair proteins to the damage, destabilizes Mfd, which dissociates from DNA. The net result is preferential, relatively rapid repair of transcription‐blocking damage.
Frailty is a state of vulnerability to poor resolution of homeostasis following a stressor event, such as chemotherapy or cancer surgery. Better knowledge of the epidemiology of frailty could help ...drive a global cancer care strategy for older people. The aim of this review was to establish the prevalence and outcomes of frailty and pre-frailty in older cancer patients.
Observational studies that reported data on the prevalence and/or outcomes of frailty in older cancer patients with any stage of solid or haematological malignancy were considered. We searched Medline, CINAHL, Cochrane Library, EMBASE, Web of Science, Allied and Complementary medicine, Psychinfo and ProQuest (1 January 1996 to 30 June 2013). The primary outcomes were prevalence of frailty, treatment-related side-effects, unplanned hospitalization and mortality. Risk of bias was assessed using the Newcastle–Ottawa checklist.
Data from 20 studies evaluating 2916 participants are included. The median reported prevalence of frailty and pre-frailty was 42% (range 6%–86%) and 43% (range 13%–79%), respectively. A median of 32% (range 11%–78%) of patients were classified as fit. Frailty was independently associated with increased all-cause mortality adjusted 5-year hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.36–2.57. There was evidence of increased risk of postoperative mortality for both frailty (adjusted 30-day HR 2.67, 95% CI 1.08–6.62) and pre-frailty (adjusted HR 2.33, 95% CI 1.20–4.52). Treatment complications were more frequent in those with frailty, including intolerance to cancer treatment (adjusted odds ratio 4.86, 95% CI 2.19–10.78) and postoperative complications (adjusted 30-day HR 3.19, 95% CI 1.68–6.04).
More than half of older cancer patients have pre-frailty or frailty and these patients are at increased risk of chemotherapy intolerance, postoperative complications and mortality. The findings of this review support routine assessment of frailty in older cancer patients to guide treatment decisions, and the development of multidisciplinary geriatric oncology services.
We developed a method for genome-wide mapping of DNA excision repair named XR-seq (excision repair sequencing). Human nucleotide excision repair generates two incisions surrounding the site of ...damage, creating an ∼30-mer. In XR-seq, this fragment is isolated and subjected to high-throughput sequencing. We used XR-seq to produce stranded, nucleotide-resolution maps of repair of two UV-induced DNA damages in human cells: cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts (6-4)PPs. In wild-type cells, CPD repair was highly associated with transcription, specifically with the template strand. Experiments in cells defective in either transcription-coupled excision repair or general excision repair isolated the contribution of each pathway to the overall repair pattern and showed that transcription-coupled repair of both photoproducts occurs exclusively on the template strand. XR-seq maps capture transcription-coupled repair at sites of divergent gene promoters and bidirectional enhancer RNA (eRNA) production at enhancers. XR-seq data also uncovered the repair characteristics and novel sequence preferences of CPDs and (6-4)PPs. XR-seq and the resulting repair maps will facilitate studies of the effects of genomic location, chromatin context, transcription, and replication on DNA repair in human cells.
Nucleotide excision repair is a major DNA repair mechanism in all cellular organisms. In this repair system, the DNA damage is removed by concerted dual incisions bracketing the damage and at a ...precise distance from the damage. Here, we review the basic mechanisms of excision repair in Escherichia coli and humans and the recent genome-wide mapping of DNA damage and repair in these organisms at single-nucleotide resolution.
Introduction
In 2008, the UK National Osteoporosis Guideline Group (NOGG) produced a guideline on the prevention and treatment of osteoporosis, with an update in 2013. This paper presents a major ...update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men age 50 years or over.
Methods
Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence.
Results
Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment, lifestyle measures and pharmacological interventions, duration and monitoring of bisphosphonate therapy, glucocorticoid-induced osteoporosis, osteoporosis in men, postfracture care and intervention thresholds.
Conclusion
The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals who are involved in its management.
The mammalian circadian clock is based on a transcription-translation feedback loop (TTFL) consolidated by secondary loops. In the primary TTFL, the circadian locomotor output cycles kaput ...(CLOCK)–brain and muscle Arnt-like protein-1 (BMAL1) heterodimer acts as the transcriptional activator, and Cryptochrome (CRY) and Period (PER) proteins function as repressors. PER represses by displacing CLOCK–BMAL1 from promoters in a CRY-dependent manner. Interestingly, genes with complex promoters may either be repressed or de-repressed by PER, depending on the particular promoter regulatory elements. Here, using mouse cell lines with defined knockout mutations in clock genes, RNA-seq, ChIP-seq, and reporter gene assays coupled with measurements of DNA–protein interactions in nuclear extracts, we elucidate the dual functions of PER as repressor and de-repressor in a context-dependent manner.
The mammalian circadian clock is based on a transcription-translation feedback loop (TTFL) in which CLOCK and BMAL1 proteins act as transcriptional activators of Cryptochrome and Period genes, which ...encode proteins that repress CLOCK-BMAL1 with a periodicity of ∼ 24 h. In this model, the mechanistic roles of CRY and PER are unclear. Here, we used a controlled targeting system to introduce CRY1 or PER2 into the nuclei of mouse cells with defined circadian genotypes to characterize the functions of CRY and PER. Our data show that CRY is the primary repressor in the TTFL: It binds to CLOCK-BMAL1 at the promoter and inhibits CLOCK-BMAL1-dependent transcription without dissociating the complex ("blocking"-type repression). PER alone has no effect on CLOCK-BMAL1-activated transcription. However, in the presence of CRY, nuclear entry of PER inhibits transcription by displacing CLOCK-BMAL1 from the promoter ("displacement"-type repression). In light of these findings, we propose a new model for the mammalian circadian clock in which the negative arm of the TTFL proceeds by two different mechanisms during the circadian cycle.
Abstract Since the launch in 2008 by the National Osteoporosis Guideline Group (NOGG), of guidance for the diagnosis and management of osteoporosis in postmenopausal women and older men in the UK ...there have been significant advances in risk assessment and treatment. These have been incorporated into an updated version of the guideline, with an additional focus on the management of glucocorticoid-induced osteoporosis, the role of calcium and vitamin D therapy and the benefits and risks of long-term bisphosphonate therapy. The updated guideline is summarised below. The recommendations in the guideline are intended to aid management decisions but do not replace the need for clinical judgement in the care of individuals in clinical practice.
Photolyases and cryptochrome blue-light photoreceptors are evolutionarily related flavoproteins that perform distinct functions. Photolyases repair UV-damaged DNA in many species from bacteria to ...plants and animals. Cryptochromes regulate growth and development in plants and the circadian clock in animals. Recently, a new branch of the photolyase/cryptochrome family was identified. Members of this branch exhibited no or trace levels of DNA repair activity in vivo and in vitro and, therefore, were considered to be cryptochromes, and they were named cryptochrome-DASH. Here, we show that Cry-DASH proteins from bacterial, plant, and animal sources actually are photolyases with high degree of specificity for cyclobutane pyrimidine dimers in ssDNA.
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