University of Sussex
Reynolds,_John_J..pdf (7.18 MB)

Investigating the link between defective DNA end-processing and human neurological disease

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posted on 2023-06-07, 16:22 authored by John Joseph Reynolds
DNA single-strand breaks (SSB) are the most commonly occurring type of DNA damage arising in a cell and they are repaired by rapid repair pathways collectively termed single-strand break repair (SSBR). Recently several rare hereditary neurodegenerative disorders with mutations in genes associated with SSBR, spinocerebellar ataxia and axonal neuropathy-1 (SCAN1), ataxia oculomotor apraxia-1 (AOA1) and microcephaly with early onset seizures and developmental delay (MCSZ), have been discovered. A striking aspect that these disorders have in common is that they are all caused by mutations in end-processing factors. The majority of SSBs that arise via endogenous damage have ‘dirty’ termini and require end-processing to restore DNA ends with conventional ‘ligatable’ chemistry. Another common feature of these end-processing enzymes is their association with XRCC1, a scaffolding protein that is a core component of SSBR. Complete loss of XRCC1 is embryonically lethal and the conditional deletion of XRCC1 in the developing mouse brain leads to persistent DNA damage, cerebellar interneurons loss and abnormal hippocampal function resulting in behavioural abnormalities such as seizures and episodic epilepsy. Taken together these observations suggest that neural cells are exquisitely sensitive to defects in chromosomal SSBR. In my thesis, I will describe biochemical and cellular data on lymphoblastoid and fibroblast cell lines derived from patients with mutations in the end-processing factors aprataxin (APTX is mutated in AOA1). I will include data showing that aprataxin is required for the short-patch SSBR of abortive ligation intermediates in vitro and that repair arrests in AOA1 cell lines due to insufficient levels of non-adenylated DNA ligase.


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University of Sussex

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