Human DNA helicase B (HELB/HDHB) regulates DNA replication through association with human DNA polymerase α-primase. In the present study, an 866-base pair (bp) of the 5′-flanking region of the human HELB gene-containing Luciferase (Luc) reporter plasmid, pHDHB-Luc was transfected into various cell lines and Luc activity was analyzed. Deletion analyses revealed that a 121-bp containing the major transcription start site (TSS) was essential for the basal promoter activity in all tested cells. TF-SEARCH analysis indicated that GC-box/Sp1 and duplicated GGAA-motifs containing putative STAT-x and c-ETS binding sites are located close to the TSS. Furthermore, chromatin immunoprecipitation (ChIP) analysis showed that PU.1 and Sp1 bind to the 121-bp region. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analyses showed the HELB gene and protein expression was up-regulated by trans-Resveratrol (Rsv) treatment in HeLa S3 cells. Moreover, transfection experiment indicated that mutations on the GC-boxes and the duplicated GGAA-motif greatly reduced promoter activity and the response to Rsv in HeLa S3 cells. These results suggest that Rsv, which is a natural compound that has been found to elongate the lifespan of various organisms, regulates HELB promoter activity through co-operation of the GC-boxes and the duplicated GGAA-motif in the 121-bp.
A natural compound Resveratrol (Rsv), which is found in high concentrations in grape skins and red wine, is expected to be a leading drug for elongating the life span and preventing oncogenesis. This compound is reported to have various beneficial effects on health, including the activation of complex I and anti-oxidative stress. We have been focusing on the regulation of the expression of human genes and have analyzed the promoter activities of several genes that encode DNA repair-functionassociated protein factors. Notably, the 5'-upstream regions of these genes very frequently contain the duplicated GGAA-motifs that allow HeLa S3 cells to respond to Rsv. In this review, we discuss the molecular mechanism by which Rsv regulates the expression of genes associated with DNA repair. We suggest the possibility of developing new anti-aging/cancer drugs without harmful side effects, based on a new concept of ameliorating or maintaining the cellular NAD + /NADH level.
Recent analyses of the whole genome sequencing data enable us to predict cancer incidence for healthy people at present. In addition, metabolome analyses rediscovered that "cancer is a metabolic disease". Importantly, it has been suggested that mitochondrial dysfunction might precede the metabolic change. In this chapter, we would discuss if "cancer is a transcriptional disease". Analyzing 5′-upstream non-protein-encoding regions of the human mitochondrial function-associated genes, we speculate that mitochondrial functions could be recovered or improved at a transcriptional level. In the near future, novel chemo-/gene-therapies might be applied to treat cancer patient converting cancerous cells into normal differentiated cells.
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