SummaryThe cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPC-inducing agents due to a defect in DNA replication fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.
Objective: To improve medulloblastoma proton therapy. Although considered ideal for proton therapy, there are potential disadvantages. Expected benefits include reduced radiation-induced cancer and circulatory complications, while avoiding small brain volumes of dose in-homogeneity when compared with conventional X-rays. Several aspects of proton therapy might contribute to reduced tumour control due to (a) the use of more homogenous dose levels which can result in under-dosage, (b) differences in relative biological effectiveness (RBE) between that prescription RBE of 1.1 and the RBE of brain and spinal cord (likely to exceed 1.1) and in medulloblastoma cells (where RBE is likely to be below 1.1). Such changes, although speculative for RBE, might result in potential underdosage of tumour cells and a higher bio-effect in brain tissue. Methods: Dose distributions for X-ray and proton treatment are compared, with allocation of likely RBE values for fast growing medullolastoma cells and stable central nervous system tissue. Results: These physical and radiobiological factors are shown to combine to give a higher risk of tumour recurrence with further risks on tumour control when dose reduction schedules used for X-ray therapy are replicated for proton therapy for ''low-risk'' patients. Conclusion: The dose distributions and prescribed doses of proton therapy, taking into account RBE, in children and adults with medulloblastoma, need to be reconsidered. The medulloblastoma tumour, which most commonly arises in childhood, is normally treated by subtotal surgical excision, with or without cytotoxic chemotherapy, but always with post-operative radiotherapy to the whole brain and spinal column, which results in impressive cure rates of around 70-80%. The highest radiation dose is given to the posterior fossa of the brain where the tumour originates, but a lower dose is given to the remaining brain and spinal cord tissues using X-rays or protons [1][2][3][4] because of the risk of later tumour growth in these regions as a consequence of tumour cells deposited on neural surfaces due to spread of the tumour via the cerebrospinal fluid (CSF). Unlike X-rays, a posterior spinal proton beam using a selected energy range does not incur an ''exit beam'' dose to organs anterior to the spinal tissues, and so reduces the risk of future carcinogenesis [5], circulatory complications [6] and potentially some cases of female infertility. Such complications can occur after a relatively low dose of Xray exposure, such as in the 5-30 Gy range.Proton therapy dose distributions depend on the Bragg peak effect and can be delivered using broad ''passively scattered'' beams or by multiple individual pencil beams. Spread of the tumour from the primary site occurs through the CSF to other areas of the brain or spine. The aim of proton therapy is to deliver a homogeneous dose across the brain and spinal cord. The CSF-containing regions must be included, especially the cisterns and ventricles of the brain, and all subarachnoid spaces, including th...
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