Scholarly Works - MRC Cancer Unit
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Item Open Access Published version Peer-reviewed Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells.(Elsevier BV, 2018-01) Gonçalves, Emanuel; Sciacovelli, Marco; Costa, Ana SH; Tran, Maxine Gia Binh; Johnson, Timothy Isaac; Machado, Daniel; Frezza, Christian; Saez-Rodriguez, Julio; Frezza, Christian [0000-0002-3293-7397]Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.Item Open Access Accepted version Peer-reviewed Care in the last days of life.(Mark Allen Group, 2016-04) Bowers, Ben; Bowers, Ben [0000-0001-6772-2620]In December 2015, the National Institute for Health and Care Excellence (NICE) introduced new evidence-based guidance on the ‘Care of dying adults in the last days of life’. Arguably, since discontinuation of the Liverpool Care Pathway (LCP), there has been a need for concise, evidence-based guidance on clinical interventions in the last days of life. The LCP was withdrawn owing to concerns that it had led to cases of food and fluids being withheld and situations where medications could have been overprescribed, resulting in unnecessary suffering or over-sedation of the dying person (NICE, 2015). In their review of the LCP, Neuberger at al (2013) identified that it was the lack of staff training, supervision, and poor or indiscriminate implementation that undermined the principles of the LCP rather than the tool offering a poor clinical framework. It was recommended that the tool be replaced by an individualised end-of-life care plan encompassing five key priorities for care (Leadership Alliance for the Care of Dying People, 2014).Item Open Access Accepted version Peer-reviewed Recognising metastatic spinal cord compression.(Mark Allen Group, 2015-04) Bowers, Ben; Bowers, Ben [0000-0001-6772-2620]Metastatic spinal cord compression (MSCC) is a potentially life changing oncological emergency. Neurological function and quality of life can be preserved if patients receive an early diagnosis and rapid access to acute interventions to prevent or reduce nerve damage. Symptoms include developing spinal pain, numbness or weakness in arms or legs, or unexplained changes in bladder and bowel function. Community nurses are well placed to pick up on the 'red flag' symptoms of MSCC and ensure patients access prompt, timely investigations to minimise damage.Item Open Access Accepted version Peer-reviewed The ubiquitin family meets the Fanconi anemia proteins.(Elsevier BV, 2016) Renaudin, Xavier; Koch Lerner, Leticia; Menck, Carlos Frederico Martins; Rosselli, Filippo; Renaudin, Xavier [0000-0002-2970-6010]Fanconi anaemia (FA) is a hereditary disorder characterized by bone marrow failure, developmental defects, predisposition to cancer and chromosomal abnormalities. FA is caused by biallelic mutations that inactivate genes encoding proteins involved in replication stress-associated DNA damage responses. The 20 FANC proteins identified to date constitute the FANC pathway. A key event in this pathway involves the monoubiquitination of the FANCD2-FANCI heterodimer by the collective action of at least 10 different proteins assembled in the FANC core complex. The FANC core complex-mediated monoubiquitination of FANCD2-FANCI is essential to assemble the heterodimer in subnuclear, chromatin-associated, foci and to regulate the process of DNA repair as well as the rescue of stalled replication forks. Several recent works have demonstrated that the activity of the FANC pathway is linked to several other protein post-translational modifications from the ubiquitin-like family, including SUMO and NEDD8. These modifications are related to DNA damage responses but may also affect other cellular functions potentially related to the clinical phenotypes of the syndrome. This review summarizes the interplay between the ubiquitin and ubiquitin-like proteins and the FANC proteins that constitute a major pathway for the surveillance of the genomic integrity and addresses the implications of their interactions in maintaining genome stability.Item Open Access Published version Peer-reviewed Reproducibility in Research: Systems, Infrastructure, Culture(Ubiquity Press, 2017-11-09) Crick, T; Hall, BA; Ishtiaq, S; Hall, Benjamin [0000-0003-0355-2946]The reproduction and replication of research results has become a major issue for a number of scientific disciplines. In computer science and related computational disciplines such as systems biology, the challenges closely revolve around the ability to implement (and exploit) novel algorithms and models. Taking a new approach from the literature and applying it to a new codebase frequently requires local knowledge missing from the published manuscripts and transient project websites. Alongside this issue, benchmarking, and the lack of open, transparent and fair benchmark sets present another barrier to the verification and validation of claimed results. In this paper, we outline several recommendations to address these issues, driven by specific examples from a range of scientific domains. Based on these recommendations, we propose a high-level prototype open automated platform for scientific software development which effectively abstracts specific dependencies from the individual researcher and their workstation, allowing easy sharing and reproduction of results. This new e-infrastructure for reproducible computational science offers the potential to incentivise a culture change and drive the adoption of new techniques to improve the quality and efficiency – and thus reproducibility – of scientific exploration.Item Open Access Accepted version Peer-reviewed Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer(Wiley-Blackwell, 2017-10) Sciacovelli, M; Frezza, C; Frezza, Christian [0000-0002-3293-7397]Several lines of evidence indicate that during transformation epithelial cancer cells can acquire mesenchymal features via a process called epithelial-to-mesenchymal transition (EMT). This process endows cancer cells with increased invasive and migratory capacity, enabling tumour dissemination and metastasis. EMT is associated with a complex metabolic reprogramming, orchestrated by EMT transcription factors, which support the energy requirements of increased motility and growth in harsh environmental conditions. The discovery that mutations in metabolic genes such as FH, SDH and IDH activate EMT provided further evidence that EMT and metabolism are intertwined. In this review, we discuss the role of EMT in cancer and the underpinning metabolic reprogramming. We also put forward the hypothesis that, by altering chromatin structure and function, metabolic pathways engaged by EMT are necessary for its full activation.Item Open Access Accepted version Peer-reviewed Extracellular vesicles are independent metabolic units with asparaginase activity.(Springer Science and Business Media LLC, 2017-09) Iraci, Nunzio; Gaude, Edoardo; Leonardi, Tommaso; Costa, Ana SH; Cossetti, Chiara; Peruzzotti-Jametti, Luca; Bernstock, Joshua D; Saini, Harpreet K; Gelati, Maurizio; Vescovi, Angelo Luigi; Bastos, Carlos; Faria, Nuno; Occhipinti, Luigi G; Enright, Anton J; Frezza, Christian; Pluchino, Stefano; Iraci, Nunzio [0000-0003-2146-9329]; Peruzzotti-Jametti, Luca [0000-0002-9396-5607]; Bernstock, Joshua D [0000-0002-7814-3867]; Frezza, Christian [0000-0002-3293-7397]Extracellular vesicles (EVs) are membrane particles involved in the exchange of a broad range of bioactive molecules between cells and the microenvironment. Although it has been shown that cells can traffic metabolic enzymes via EVs, much remains to be elucidated with regard to their intrinsic metabolic activity. Accordingly, herein we assessed the ability of neural stem/progenitor cell (NSC)-derived EVs to consume and produce metabolites. Our metabolomics and functional analyses both revealed that EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1). Critically, we show that Asrgl1 activity is selective for asparagine and is devoid of glutaminase activity. We found that mouse and human NSC EVs traffic Asrgl1. Our results demonstrate, for the first time, that NSC EVs function as independent metabolic units that are able to modify the concentrations of critical nutrients, with the potential to affect the physiology of their microenvironment.Item Open Access Accepted version Peer-reviewed A qualitative study of community nurses' decision-making around the anticipatory prescribing of end-of-life medications.(Wiley, 2017-10) Bowers, Ben; Redsell, Sarah A; Bowers, Ben [0000-0001-6772-2620]; Redsell, Sarah A [0000-0002-2176-2325]AIMS: The aim of this study was to explore community nurses' decision-making processes around the prescribing of anticipatory medications for people who are dying. BACKGROUND: Community nurses frequently initiate the prescribing of anticipatory medications to help control symptoms in those who are dying. However, little is known about their decision-making processes in relation to when they instigate anticipatory prescribing and their discussions with families and General Practitioners. DESIGN: A qualitative interpretive descriptive enquiry. METHODS: A purposive sample of 11 Community Palliative Nurses and District Nurses working in one geographical area participated. Data were collected between March and June 2016 via audio recorded semi-structured interviews and analysed inductively using Braun and Clarke's thematic analysis. RESULTS: Three themes were identified: (1) Drugs as a safety net. Anticipatory medications give nurses a sense of control in last days of life symptom management; (2) Reading the situation. The nurse judges when to introduce conversations around anticipatory medications, balancing the need for discussion with the dying person and their family's likely response; (3) Playing the game. The nurse owns the decision to initiate anticipatory medication prescribing and carefully negotiates with the General Practitioner. CONCLUSION: Nurses view pain control through prescribed medication as key to symptom management for dying people. Consequently, they own the role of ascertaining when to initiate discussions with families about anticipatory medicines. Nurses believe they advocate for dying person and their families' needs and lead negotiations with General Practitioners for medications to go into the home. This nurse led care alters the traditional boundaries of the General Practitioners-nurse professional relationship.Item Open Access Published version Peer-reviewed Mammalian Circadian Period, But Not Phase and Amplitude, Is Robust Against Redox and Metabolic Perturbations(Mary Ann Liebert, 2017-06-26) Putker, M; Crosby, P; Feeney, KA; Hoyle, NP; Costa, ASH; Gaude, E; Frezza, C; O'Neill, JS; Frezza, Christian [0000-0002-3293-7397]; O'Neill, John [0000-0003-2204-6096]$\textit{Aims:}$ Circadian rhythms permeate all levels of biology to temporally regulate cell and whole-body physiology, although the cell-autonomous mechanism that confers ~24-h periodicity is incompletely understood. Reports describing circadian oscillations of over-oxidized peroxiredoxin abundance have suggested that redox signaling plays an important role in the timekeeping mechanism. Here, we tested the functional contribution that redox state and primary metabolism make to mammalian cellular timekeeping. $\textit{Results:}$ We found a circadian rhythm in flux through primary glucose metabolic pathways, indicating rhythmic NAD(P)H production. Using pharmacological and genetic perturbations, however, we found that timekeeping was insensitive to changes in glycolytic flux, whereas oxidative pentose phosphate pathway (PPP) inhibition and other chronic redox stressors primarily affected circadian gene expression amplitude, not periodicity. Finally, acute changes in redox state decreased PER2 protein stability, phase dependently, to alter the subsequent phase of oscillation. $\textit{Innovation:}$ Circadian rhythms in primary cellular metabolism and redox state have been proposed to play a role in the cellular timekeeping mechanism. We present experimental data testing that hypothesis. $\textit{Conclusion:}$ Circadian flux through primary metabolism is cell autonomous, driving rhythmic NAD(P)(+) redox cofactor turnover and maintaining a redox balance that is permissive for circadian gene expression cycles. Redox homeostasis and PPP flux, but not glycolysis, are necessary to maintain clock amplitude, but neither redox nor glucose metabolism determines circadian period. Furthermore, cellular rhythms are sensitive to acute changes in redox balance, at least partly through regulation of PER protein. Redox and metabolic state are, thus, both inputs and outputs, but not state variables, of cellular circadian timekeeping.Item Open Access Published version Peer-reviewed A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy(Cold Spring Harbor Laboratory Press, 2017-07-01) Noorani, A; Bornschein, J; Lynch, AG; Secrier, M; Achilleos, A; Eldridge, M; Bower, L; Weaver, JMJ; Crawte, J; Ong, C-A; Shannon, N; MacRae, S; Grehan, N; Nutzinger, B; O'Donovan, M; Hardwick, R; Tavaré, S; Fitzgerald, RC; Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium; Lynch, Andy [0000-0002-7876-7338]; Eldridge, Matthew [0000-0002-5799-8911]; Fitzgerald, Rebecca [0000-0002-3434-3568]The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.Item Open Access Published version Peer-reviewed Decision making, quality of life and prophylactic gastrectomy in carriers of pathogenic CDH1 mutations(AME Publishing Company, 2017-03-23) Roberts, G; Hardwick, R; Fitzgerald, RC; Fitzgerald, Rebecca [0000-0002-3434-3568]Item Open Access Published version Peer-reviewed Past, present and future of Barrett's oesophagus(Elsevier, 2017-02-16) Tan, WK; di Pietro, M; Fitzgerald, RC; Di Pietro, Massimiliano [0000-0003-4866-7026]; Fitzgerald, Rebecca [0000-0002-3434-3568]Barrett's oesophagus is a condition which predisposes towards development of oesophageal adenocarcinoma, a highly lethal tumour which has been increasing in incidence in the Western world over the past three decades. There have been tremendous advances in the field of Barrett's oesophagus, not only in diagnostic modalities, but also in therapeutic strategies available to treat this premalignant disease. In this review, we discuss the past, present and future of Barrett's oesophagus. We describe the historical and new evolving diagnostic criteria of Barrett's oesophagus, while also comparing and contrasting the British Society of Gastroenterology guidelines, American College of Gastroenterology guidelines and International Benign Barrett's and CAncer Taskforce (BOBCAT) for Barrett's oesophagus. Advances in endoscopic modalities such as confocal and volumetric laser endomicroscopy, and a non-endoscopic sampling device, the Cytosponge, are described which could aid in identification of Barrett's oesophagus. With regards to therapy we review the evidence for the utility of endoscopic mucosal resection and radiofrequency ablation when coupled with better characterization of dysplasia. These endoscopic advances have transformed the management of Barrett's oesophagus from a primarily surgical disease into an endoscopically managed condition.Item Open Access Published version Peer-reviewed Past, present and future of Barrett's oesophagus(Elsevier, 2017-02-16) Tan, WK; di Pietro, M; Fitzgerald, Rebecca; Fitzgerald, Rebecca [0000-0002-3434-3568]Barrett's oesophagus is a condition which predisposes towards development of oesophageal adenocarcinoma, a highly lethal tumour which has been increasing in incidence in the Western world over the past three decades. There have been tremendous advances in the field of Barrett's oesophagus, not only in diagnostic modalities, but also in therapeutic strategies available to treat this premalignant disease. In this review, we discuss the past, present and future of Barrett's oesophagus. We describe the historical and new evolving diagnostic criteria of Barrett's oesophagus, while also comparing and contrasting the British Society of Gastroenterology guidelines, American College of Gastroenterology guidelines and International Benign Barrett's and CAncer Taskforce (BOBCAT) for Barrett's oesophagus. Advances in endoscopic modalities such as confocal and volumetric laser endomicroscopy, and a non-endoscopic sampling device, the Cytosponge, are described which could aid in identification of Barrett's oesophagus. With regards to therapy we review the evidence for the utility of endoscopic mucosal resection and radiofrequency ablation when coupled with better characterization of dysplasia. These endoscopic advances have transformed the management of Barrett's oesophagus from a primarily surgical disease into an endoscopically managed condition.Item Open Access Accepted version Peer-reviewed Bringing LTL Model Checking to Biologists(Springer) Ahmed, Z; Benque, D; Berezin, S; Dahl, ACE; Fisher, Jasmin; Hall, Benjamin Andrew; Ishtiaq, S; Nanavati, J; Piterman, N; Riechert, M; Skoblov, N; Hall, Benjamin Andrew [0000-0003-0355-2946]The BioModelAnalyzer (BMA) is a web based tool for the development of discrete models of biological systems. Through a graphical user interface, it allows rapid development of complex models of gene and protein interaction networks and stability analysis without requiring users to be proficient computer programmers. Whilst stability is a useful specification for testing many systems, testing temporal specifications in BMA presently requires the user to perform simulations. Here we describe the LTL module, which includes a graphical and natural language interfaces to testing LTL queries. The graphical interface allows for graphical construction of the queries and presents results visually in keeping with the current style of BMA. The Natural language interface complements the graphical interface by allowing a gentler introduction to formal logic and exposing educational resources.Item Open Access Published version Peer-reviewed Mitochondrial metabolites: Undercover signalling molecules(The Royal Society Publishing, 2017-04-06) Frezza, C; Frezza, Christian [0000-0002-3293-7397]Mitochondria are one of most characterized metabolic hubs of the cell. Here, crucial biochemical reactions occur and most of the cellular adenosine triphosphate (ATP) is produced. In addition, mitochondria act as signalling platforms and communicate with the rest of the cell by modulating calcium fluxes, by producing free radicals, and by releasing bioactive proteins. It is emerging that mitochondrial metabolites can also act as second messengers and can elicit profound (epi)genetic changes. This review describes the many signalling functions of mitochondrial metabolites under normal and stress conditions, focusing on metabolites of the tricarboxylic acid cycle. We provide a new framework for understanding the role of mitochondrial metabolism in cellular pathophysiology.Item Open Access Published version Peer-reviewed Fumarate drives EMT in renal cancer(Nature Publishing Group, 2017-01-01) Sciacovelli, M; Frezza, C; Frezza, Christian [0000-0002-3293-7397]Item Open Access Published version Peer-reviewed Epigenetic determinants of metastasis.(Wiley, 2017-01) Patel, Saroor A; Vanharanta, Sakari; Vanharanta, Sakari [0000-0001-5619-7963]Genetic analyses of cancer progression in patient samples and model systems have thus far failed to identify specific mutational drivers of metastasis. Yet, at least in experimental systems, metastatic cancer clones display stable traits that can facilitate progression through the many steps of metastasis. How cancer cells establish and maintain the transcriptional programmes required for metastasis remains mostly unknown. Emerging evidence suggests that metastatic traits may arise from epigenetically altered transcriptional output of the oncogenic signals that drive tumour initiation and early progression. Molecular dissection of such mechanisms remains a central challenge for a comprehensive understanding of the origins of metastasis.Item Open Access Accepted version Peer-reviewed Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study.(Elsevier BV, 2017-01) Ross-Innes, Caryn S; Chettouh, Hamza; Achilleos, Achilleas; Galeano-Dalmau, Nuria; Debiram-Beecham, Irene; MacRae, Shona; Fessas, Petros; Walker, Elaine; Varghese, Sibu; Evan, Theodore; Lao-Sirieix, Pierre S; O'Donovan, Maria; Malhotra, Shalini; Novelli, Marco; Disep, Babett; Kaye, Phillip V; Lovat, Laurence B; Haidry, Rehan; Griffin, Michael; Ragunath, Krish; Bhandari, Pradeep; Haycock, Adam; Morris, Danielle; Attwood, Stephen; Dhar, Anjan; Rees, Colin; Rutter, Matt D; Ostler, Richard; Aigret, Benoit; Sasieni, Peter D; Fitzgerald, Rebecca C; BEST2 study group; Fitzgerald, Rebecca [0000-0002-3434-3568]BACKGROUND: Barrett's oesophagus predisposes to adenocarcinoma. However, most patients with Barrett's oesophagus will not progress and endoscopic surveillance is invasive, expensive, and fraught by issues of sampling bias and the subjective assessment of dysplasia. We investigated whether a non-endoscopic device, the Cytosponge, could be coupled with clinical and molecular biomarkers to identify a group of patients with low risk of progression suitable for non-endoscopic follow-up. METHODS: In this multicentre cohort study (BEST2), patients with Barrett's oesophagus underwent the Cytosponge test before their surveillance endoscopy. We collected clinical and demographic data and tested Cytosponge samples for a molecular biomarker panel including three protein biomarkers (P53, c-Myc, and Aurora kinase A), two methylation markers (MYOD1 and RUNX3), glandular atypia, and TP53 mutation status. We used a multivariable logistic regression model to compute the conditional probability of dysplasia status. We selected a simple model with high classification accuracy and applied it to an independent validation cohort. The BEST2 study is registered with ISRCTN, number 12730505. FINDINGS: The discovery cohort consisted of 468 patients with Barrett's oesophagus and intestinal metaplasia. Of these, 376 had no dysplasia and 22 had high-grade dysplasia or intramucosal adenocarcinoma. In the discovery cohort, a model with high classification accuracy consisted of glandular atypia, P53 abnormality, and Aurora kinase A positivity, and the interaction of age, waist-to-hip ratio, and length of the Barrett's oesophagus segment. 162 (35%) of 468 of patients fell into the low-risk category and the probability of being a true non-dysplastic patient was 100% (99% CI 96-100) and the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 0% (0-4). 238 (51%) of participants were classified as of moderate risk; the probability of having high-grade dysplasia was 14% (9-21). 58 (12%) of participants were classified as high-risk; the probability of having non-dysplastic endoscopic biopsies was 13% (5-27), whereas the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 87% (73-95). In the validation cohort (65 patients), 51 were non-dysplastic and 14 had high-grade dysplasia. In this cohort, 25 (38%) of 65 patients were classified as being low-risk, and the probability of being non-dysplastic was 96·0% (99% CI 73·80-99·99). The moderate-risk group comprised 27 non-dysplastic and eight high-grade dysplasia cases, whereas the high-risk group (8% of the cohort) had no non-dysplastic cases and five patients with high-grade dysplasia. INTERPRETATION: A combination of biomarker assays from a single Cytosponge sample can be used to determine a group of patients at low risk of progression, for whom endoscopy could be avoided. This strategy could help to avoid overdiagnosis and overtreatment in patients with Barrett's oesophagus. FUNDING: Cancer Research UK.Item Open Access Published version Peer-reviewed High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy.(Oxford University Press, 2016-11-02) Short, Judith M; Liu, Yang; Chen, Shaoxia; Soni, Neelesh; Madhusudhan, Mallur S; Shivji, Mahmud KK; Venkitaraman, Ashok RHomologous DNA recombination (HR) by the RAD51 recombinase enables error-free DNA break repair. To execute HR, RAD51 first forms a presynaptic filament on single-stranded (ss) DNA, which catalyses pairing with homologous double-stranded (ds) DNA. Here, we report a structure for the presynaptic human RAD51 filament at 3.5-5.0Å resolution using electron cryo-microscopy. RAD51 encases ssDNA in a helical filament of 103Å pitch, comprising 6.4 protomers per turn, with a rise of 16.1Å and a twist of 56.2°. Inter-protomer distance correlates with rotation of an α-helical region in the core catalytic domain that is juxtaposed to ssDNA, suggesting how the RAD51-DNA interaction modulates protomer spacing and filament pitch. We map Fanconi anaemia-like disease-associated RAD51 mutations, clarifying potential phenotypes. We predict binding sites on the presynaptic filament for two modules present in each BRC repeat of the BRCA2 tumour suppressor, a critical HR mediator. Structural modelling suggests that changes in filament pitch mask or expose one binding site with filament-inhibitory potential, rationalizing the paradoxical ability of the BRC repeats to either stabilize or inhibit filament formation at different steps during HR. Collectively, our findings provide fresh insight into the structural mechanism of HR and its dysregulation in human disease.Item Open Access Published version Peer-reviewed Anticancer chemotherapy in teenagers and young adults: managing long term side effects.(BMJ, 2016-09-07) Ahmad, Saif S; Reinius, Marika Av; Hatcher, Helen M; Ajithkumar, Thankamma V; Ahmad, Saif [0000-0003-1020-2346]
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