RESUMO
TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive. We have solved crystal structures of a human Brf2-TBP complex bound to natural promoters, obtaining a detailed view of the molecular interactions occurring at Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Surprisingly, our structural and functional studies unravel a Brf2 redox-sensing module capable of specifically regulating Pol III transcriptional output in living cells. Furthermore, we establish Brf2 as a central redox-sensing transcription factor involved in the oxidative stress pathway and provide a mechanistic model for Brf2 genetic activation in lung and breast cancer.
Assuntos
Oxirredução , Fator de Transcrição TFIIIB/química , Fator de Transcrição TFIIIB/metabolismo , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Humanos , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , RNA Polimerase III/metabolismo , Saccharomyces cerevisiae , Alinhamento de Sequência , Transdução de SinaisRESUMO
A previously well, 14-month-old girl presented with acute decreased level of consciousness. There was no history of trauma, systemic upset or significant family history. Blood pressure was within normal range and no focal neurological deficit was elicited on examination. Neuroimaging revealed a subarachnoid haemorrhage secondary to a basilar tip aneurysm. Patient underwent endovascular embolisation with good clinical outcome. Follow-up MRI revealed anterior circulation vasospasm, and although clinically asymptomatic, she was treated with a calcium channel antagonist. She was later discharged home with no neurological deficit. Follow-up MRI 3 months following presentation suggested recurrent formation of the aneurysmal sac. The patient then underwent elective endovascular repair 2 months later and was discharged home on antiplatelet therapy with planned close outpatient clinical and radiological surveillance.
Assuntos
Embolização Terapêutica , Procedimentos Endovasculares/métodos , Aneurisma Intracraniano/terapia , Hemorragia Subaracnóidea/terapia , Terapia Antiplaquetária Dupla , Feminino , Humanos , Lactente , RecidivaRESUMO
A 13-year-old boy with a background of Prader-Willi syndrome (PWS) was admitted to the regional paediatric intensive care unit, with community-acquired pneumonia. Despite a week of intravenous antibiotics, resolution of inflammatory markers and resolving consolidation on radiograph, he remained feverish. Fever of unknown origin investigations were negative and he was diagnosed with central thermal dysregulation secondary to hypothalamic dysfunction in PWS. Following a hyperpyrexia period, secondary rhabdomyolysis and renal failure developed. This was successfully managed with active cooling, ventilation and haemofiltration. After weaning from haemofiltration, the patient was successfully extubated to non-invasive respiratory support.
Assuntos
Febre/etiologia , Síndrome de Prader-Willi/complicações , Insuficiência Respiratória/etiologia , Adolescente , Cuidados Críticos , Diagnóstico Diferencial , Febre/terapia , Humanos , Hipotermia Induzida/métodos , Masculino , Respiração com Pressão PositivaRESUMO
An 11-year-old girl was admitted for further investigation as to the cause of her bilateral papilloedema and periorbital swelling. She had a 2-week history of headache and unilateral eyelid swelling, and a 2-day history of right-sided groin swelling. CT and MRI scans revealed soft tissue adjacent to the lateral orbital walls within the extraconal lateral aspects of both orbits, more on the right than the left. The scans also revealed extensive lymphadenopathy above and below the diaphragm. The patient underwent bone marrow studies and biopsy of the lymph node in her groin. The results revealed normal bone marrow with no evidence of malignancy. The lymph node histology confirmed malignant lymphoma in keeping with B cell lymphoblastic lymphoma. The patient was started on the UKALL 2011 chemotherapy trial.