Mislocalization of XPF-ERCC1 Nuclease Contributes to Reduced DNA Repair in XP-F Patients

Xeroderma pigmentosum (XP) is caused by defects in the nucleotide excision repair (NER) pathway. NER removes helix-distorting DNA lesions, such as UV–induced photodimers, from the genome. Patients suffering from XP exhibit exquisite sun sensitivity, high incidence of skin cancer, and in some cases neurodegeneration. The severity of XP varies tremendously depending upon which NER gene is mutated and how severely the mutation affects DNA repair capacity. XPF-ERCC1 is a structure-specific endonuclease essential for incising the damaged strand of DNA in NER. Missense mutations in XPF can result not only in XP, but also XPF-ERCC1 (XFE) progeroid syndrome, a disease of accelerated aging. In an attempt to determine how mutations in XPF can lead to such diverse symptoms, the effects of a progeria-causing mutation (XPFR153P) were compared to an XP–causing mutation (XPFR799W) in vitro and in vivo. Recombinant XPF harboring either mutation was purified in a complex with ERCC1 and tested for its ability to incise a stem-loop structure in vitro. Both mutant complexes nicked the substrate indicating that neither mutation obviates catalytic activity of the nuclease. Surprisingly, differential immunostaining and fractionation of cells from an XFE progeroid patient revealed that XPF-ERCC1 is abundant in the cytoplasm. This was confirmed by fluorescent detection of XPFR153P-YFP expressed in Xpf mutant cells. In addition, microinjection of XPFR153P-ERCC1 into the nucleus of XPF–deficient human cells restored nucleotide excision repair of UV–induced DNA damage. Intriguingly, in all XPF mutant cell lines examined, XPF-ERCC1 was detected in the cytoplasm of a fraction of cells. This demonstrates that at least part of the DNA repair defect and symptoms associated with mutations in XPF are due to mislocalization of XPF-ERCC1 into the cytoplasm of cells, likely due to protein misfolding. Analysis of these patient cells therefore reveals a novel mechanism to potentially regulate a cell's capacity for DNA repair: by manipulating nuclear localization of XPF-ERCC1

A Concept to Improve Care for People with Dementia

AbstractDementia is one of the severe causes of mortality in elder groups of human population, and the number of dementia patients is expected to increase all over the world. Globally, the cost to take care of patients with the illness is high. Moreover, the lives for dementia patients are commonly impacted by a variety of challenges, for example, in terms of communication, emotional behaviour, confusion and wandering. Therefore, the future aim is to develop a serious games package which can help to slow down the progression of dementia, better life for the patients and their loved one and reduce the use of medications and the cost for the government sectors. In this study, a conceptual model was formed to present the problems the dementia patients and their caregivers are facing, and non-pharmacological approaches are suggested to slow down the progression of dementia-related impairments and behavioural symptoms by using well-structured serious games with personalised data.Abstract Dementia is one of the severe causes of mortality in elder groups of human population, and the number of dementia patients is expected to increase all over the world. Globally, the cost to take care of patients with the illness is high. Moreover, the lives for dementia patients are commonly impacted by a variety of challenges, for example, in terms of communication, emotional behaviour, confusion and wandering. Therefore, the future aim is to develop a serious games package which can help to slow down the progression of dementia, better life for the patients and their loved one and reduce the use of medications and the cost for the government sectors. In this study, a conceptual model was formed to present the problems the dementia patients and their caregivers are facing, and non-pharmacological approaches are suggested to slow down the progression of dementia-related impairments and behavioural symptoms by using well-structured serious games with personalised data