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Abstract
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.
Highlights
NEURODEGENERATION: THE CEREBELLUM IS A COMMON TARGET hereditary neurological diseases in humans
Since cellular and cell-free assays using recombinant proteins have shown that proteasomal degradation of topoisomerase 1 (Top1) to a small peptide is a prerequisite for Tyrosyl DNA phosphodiesterase 1 (TDP1) action (El-Khamisy et al, 2007; Interthal et al, 2001), the increased sensitivity of CUL4B-mutated lymphoblastoid cells (LCLs) to CPT points to a role for Cullin 4B upstream of TDP1 (Fig 2)
The results suggest a slower rate of repair of hydrogen peroxide-induced deoxyribonucleic acid (DNA) damage in mtDNA in Tdp1À/À cells compared to wild-type control cells
Summary
Un-repaired DNA breaks with damaged termini have been shown to block progression of RNA polymerases in vitro (Bendixen et al, 1990) and could provide a possible explanation for neuronal cell death in case of defective TDP1. Since cellular and cell-free assays using recombinant proteins have shown that proteasomal degradation of Top to a small peptide is a prerequisite for TDP1 action (El-Khamisy et al, 2007; Interthal et al, 2001), the increased sensitivity of CUL4B-mutated LCLs to CPT points to a role for Cullin 4B upstream of TDP1 (Fig 2) This notion was reinforced by the work of Kerzendorfer et al, who showed increased levels of CPT-induced DNA breaks in CUL4B-mutated LCLs compared to wild-type cells (Kerzendorfer et al, 2010). Whether CUL4B deficiency in mice will result in growth and mental retardation is yet to be tested
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