Abstract
Author SummaryAll cells in our bodies have to cope with numerous lesions to their DNA. Cells use a battery of genes to repair DNA and maintain genome integrity. Given the importance of an intact genome, it is not surprising that genes with roles in DNA repair are mutated in many human diseases. Here, we present the results of a genome-scale DNA repair screen in human cells and discover 61 genes that have a potential role in this process. We studied in detail a previously uncharacterized gene (KIAA0415/SPG48) and demonstrated its importance for efficient DNA double strand break repair. Further analyses revealed mutations in the SPG48 gene in some patients with hereditary spastic paraplegia (HSP). We showed that SPG48 physically interacts with other HSP proteins and that patient cells are sensitive to DNA damaging drugs. Our data suggest a link between HSP and DNA repair and we propose that HSP patients should be screened for KIAA0415/SPG48 mutations in the future.
Highlights
Mutations in DNA repair genes are associated with different diseases and disorders including cancer [1], accelerated aging [2], and neuronal degeneration [3]
Our data suggest a link between hereditary spastic paraplegia (HSP) and DNA repair and we propose that HSP patients should be screened for KIAA0415/SPG48 mutations in the future
We tested the robustness of the assay by co-transfection of these cells with the ISceI expression plasmid and an endoribonuclease-prepared short interfering RNA (esiRNA) targeting Rad51, which is an essential factor for the early stages of homologous pairing and strand exchange [18]
Summary
Mutations in DNA repair genes are associated with different diseases and disorders including cancer [1], accelerated aging [2], and neuronal degeneration [3]. Neurons appear to be vulnerable to mutations in DNA repair genes, possibly due to the lack of proliferation and high oxidative stress within these cells. Several neurological diseases have been linked to defects in DNA repair such as Ataxia-telangiectasia [4], Ataxiatelangiectasia-like disorder [5], Seckel syndrome [6], Nijmegen breakage syndrome [7], and Charcot-Marie-Tooth syndrome [8]. DSBs are repaired mainly via two parallel pathways: homologous recombination and nonhomologous end joining (NHEJ). Repair via homologous recombination typically restores the genetic information, whereas repair via NHEJ often leads to mutations [10,11]
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