Abstract
BackgroundDNA helicases are ubiquitous enzymes that unwind DNA in an ATP-dependent and directionally specific manner. Unwinding of double-stranded DNA is essential for the processes of DNA repair, recombination, transcription, and DNA replication. Five human DNA helicases sharing sequence similarity with the E. coli RecQ helicase have been identified. Three of the human RecQ helicases are implicated in hereditary diseases (Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome) which display clinical symptoms of premature aging and cancer. RECQ1 helicase is the most highly expressed of the human RecQ helicases; however, a genetic disease has yet not been linked to mutations in the RECQ1 gene, and the biological functions of human RECQ1 in cellular DNA metabolism are not known.Methodology/Principal FindingsIn this study, we report that RECQ1 becomes phosphorylated upon DNA damage and forms irradiation-induced nuclear foci that associate with chromatin in human cells. Depletion of RECQ1 renders human cells sensitive to DNA damage induced by ionizing radiation or the topoisomerase inhibitor camptothecin, and results in spontaneous γ-H2AX foci and elevated sister chromatid exchanges, indicating aberrant repair of DNA breaks. Consistent with a role in homologous recombinational repair, endogenous RECQ1 is associated with the strand exchange protein Rad51 and the two proteins directly interact with high affinity.Conclusion/SignificanceCollectively, these results provide the first evidence for a role of human RECQ1 in the response to DNA damage and chromosomal stability maintenance and point to the vital importance of RECQ1 in genome homeostasis.
Highlights
It is believed that RecQ helicases have multiple roles in three facets of DNA metabolism, S-phase checkpoint, and telomere maintenance; they are considered caretakers of the genome [1,2]
We set out to characterize the importance of human RECQ1 in the DNA damage response in order to obtain an understanding of its biological relevance in cellular DNA metabolism
Since an effect of RECQ1 deficiency on growth properties had not been previously examined, we evaluated several biological parameters pertaining to growth and proliferation in human cells depleted of RECQ1 by RNA intereference. siRNA depletion of RECQ1 during a 48 h time period led to a decrease of .90% of RECQ1 compared to control as observed by Western blotting (Fig. 3A)
Summary
It is believed that RecQ helicases have multiple roles in three facets of DNA metabolism (repair, replication and recombination), S-phase checkpoint, and telomere maintenance; they are considered caretakers of the genome [1,2]. Three of the five human RecQ genes, designated BLM, WRN and RECQ4, have been genetically linked to the autosomal recessive diseases Bloom Syndrome (BS), Werner Syndrome (WS) and Rothmund-Thomson Syndrome (RTS), respectively. All three of these rare human diseases are characterized by a predisposition to cancer and chromosome instability, but the clinical features and cellular phenotypes are different from each other, suggesting unique roles of BLM, WRN, and RECQ4 helicases as tumor suppressors. These results provide the first evidence for a role of human RECQ1 in the response to DNA damage and chromosomal stability maintenance and point to the vital importance of RECQ1 in genome homeostasis
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