To live or to die: a matter of processing damaged DNA termini in neurons.
Bottom Line: Defects in the repair of deoxyribonucleic acid (DNA) damage underpin several hereditary neurological diseases in humans.Of the different activities that repair chromosomal DNA breaks, defects in resolving damaged DNA termini are among the most common causes of neuronal cell death.Here, the molecular mechanisms of some of the DNA end processing activities are reviewed and the association with human neurodegenerative disease is discussed.
Affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Brighton, UK. email@example.comShow MeSH
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Mentions: One of the most common forms of damaged DNA termini induced by ROS is 3′-phosphate, which is a major substrate for polynucleotide kinase phosphatase (PNKP, Chen et al, 1991). Importantly, the product of TDP1 activity is 3′-phosphate and 5′-hydroxyl termini, both of which require the 3′-phosphatase and 5′-kinase activities of PNKP to create ligatable termini (Fig 2). Mutations in PNKP were recently identified in several pedigrees of Arabic and European origin that possess an autosomal recessive disorder, which features microcephaly, infantile-onset seizures, and developmental delay denoted MCSZ (Shen et al, 2010). Similar to SCAN1, MCSZ patients had no reported evidence for increased cancer predisposition or immunodeficiency. However, in an intriguing contrast to SCAN1, MCSZ patients lack ataxia ‘lack of muscle coordination’ and cerebellar degeneration. Western blotting and RT-PCR analyses of cells from the affected individuals suggest a correlation between the severity of clinical symptoms and expression/activity of PNKP (Shen et al, 2010). Consistent with a role for PNKP in the repair of Top1-mediated breaks, A549 cells depleted for PNKP (El-Khamisy et al, 2005) or LCLs from MCSZ patients (Shen et al, 2010) accumulate higher levels of CPT-induced DNA breaks, compared to control cells. More importantly, LCLs from MCSZ patients repair hydrogen peroxide-induced damage at a much lower rate than normal cells (Shen et al, 2010). It is worth noting that through its fork head associated (FHA) domain, PNKP interacts with XRCC1 or XRCC4, components of the single- and double-strand break repair machinery (Chappell et al, 2002; Jilani et al, 1999; Karimi-Busheri et al, 1999; Whitehouse et al, 2001).
Affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Brighton, UK. firstname.lastname@example.org