[“Molecule Used For Storing And Transferring Energy In The Body

The NER pathway is usually classied into two types, namely global genome NER, which occurs in the transcribed strand of active genes. In GGNER, the rst step is the recognition of the DNA damage by the XPCHRB A.In contrast, in TCNER the repair process is believed to be triggered by a stalled RNA polymerase, and initiation of the repair requires the proteins CSB and CSA. Afterwards, GGNER and TCNER seem to proceed in an identical way.The presence of damage is veried by XPA; the XPB helicases in complex with the TFIIH transcription factor open the DNA double helix around the damage; RPA stabilizes the open DNA by binding to the undamaged strand; the endonucleases XPF and XPG cleave the borders of the open segment in the damaged strand; the damaged segment is then removed, and the repair is completed by DNA polymerase and DNA ligase.As evidence for an association between NER and the ageing process, inherited defects in NER cause three major types of progeroid diseases in humans: XP, CS, and TTD.The severity of the symptoms in XP varies signicantly across its different types associated with defects in different genes and in general the more the mutation affects the NER pathway, the more severe the symptoms are. Moreover, multiple mutations in NER genes have been shown to result in dramatically accelerated ageing phenotypes in mice. It should also be noted that XP which is associated with a dramatic increase in skin cancers is mainly caused by a defect in GGNER; whilst the progeroid syndromes CS and TTD which show no evidence of increased risk cancer are caused mainly by defects in TCNER. This is because GGNER is responsible mainly for repairing premutagenic DNA lesions, preventing carcinogenesis; whilst TCNER is responsible mainly for repairing DNA lesions that block transcription. A particularly interesting gene for the study of the NER pathway is XPD because different point mutations in this gene are associated with different phenotypes: cancer, the TTD progeroid syndrome, or a combination of cancer and a progeroid syndrome, namely XP combined with CS. The authors proposed that the observed premature ageing of TTD mice is due to the accumulation of DNA damage, which leads to impaired transcription, apoptosis, functional decline, and depletion of cell renewal capacity.This produced mice with increased neonatal lethality and extreme cachexia.The authors observed that such progeroid NER mice share many similarities with longlived dwarf and calorierestricted mice, in particular reduced postnatal growth and small size.They argued that this is likely due to an adaptive response to genomic instability during postnatal development, which involved dampening of the somatotropic GHIGF axis, rather than due to the proliferative defects associated with premature cell senescence a common explanation for this progeroid phenotype.In this work the rate of apoptosis exceeded the rate of cell proliferation, resulting in homeostatic imbalance, and this imbalance was associated with decreased energy metabolism and reduced IGF signalling.Hence, similarly to concluded that the reduced energy metabolism is likely an adaptive response to the increased DNA damage in those mouse mutants.

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