Trends in Cell Biology
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DNA single-strand break repair and human genetic disease


      • DNA single-strand breaks (SSBs) are very common lesions, and mutations in SSB repair (SSBR) genes result in multiple genetic neurological diseases typified by neurodevelopmental dysfunction and/or neurodegeneration.
      • SSBR comprises several interlinked pathways that detect and process SSBs of a broad range of sources and chemistries, resulting from stochastic DNA damage and from intrinsic errors during ‘programmed’ DNA metabolic processes such as DNA replication, transcription, and epigenetic reprogramming.
      • SSBs are detected by poly(ADP-ribose) polymerase 1 (PARP1) and PARP2, which regulate chromatin remodelling, transcription, and the recruitment of SSBR factors such as XRCC1 protein complexes during SSBR.
      • If SSBs accumulate or persist excessively, hyperactivation of the SSB sensor PARP1 can lead to excessive NAD+ depletion, to poly(ADP-ribosylation), and to neurological dysfunction.
      DNA single-strand breaks (SSBs) are amongst the commonest DNA lesions arising in cells, with many tens of thousands induced in each cell each day. SSBs arise not only from exposure to intracellular and environmental genotoxins but also as intermediates of normal DNA metabolic processes, such as the removal of torsional stress in DNA by topoisomerase enzymes and the epigenetic regulation of gene expression by DNA base excision repair (BER). If not rapidly detected and repaired, SSBs can result in RNA polymerase stalling, DNA replication fork collapse, and hyperactivation of the SSB sensor protein poly(ADP-ribose) polymerase 1 (PARP1). The potential impact of unrepaired SSBs is illustrated by the existence of genetic diseases in which proteins involved in SSB repair (SSBR) are mutated, and which are typified by hereditary neurodevelopmental and/or neurodegenerative disease. Here, I review our current understanding of SSBR and its impact on human neurological disease, with a focus on recent developments and concepts.


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