Title:
Long non-coding RNA as an essential regulator of DNA replication stress in human malignancies

Speaker:
Yutaka Kondo
Division of Cancer Biology, Nagoya University Graduate School of Medicine

Abstract:
Recent studies have demonstrated the important multiple roles of long non-coding RNAs (lncRNAs) during oncogenic transformation. Because the coding genome accounts for a small amount of total DNA, and many mutations leading to cancer occur in the non-coding genome, it is plausible that the dysregulation of such non-coding transcribes might also affect tumor phenotypes. Indeed, to date, lncRNAs have been reported to affect diverse biological processes through the regulation of mRNA stability, RNA splicing, chromatin structure, and miRNA-mediated gene regulation by acting as miRNA sponges. Furthermore, accumulating studies have demonstrated the roles of lncRNAs in tumorigenesis; however, the precise mechanisms of many lncRNAs are still under investigation. We recently found that a subset of lncRNAs enable tumorigenesis by regulating the oncogene-induced DNA damages and/or DNA replication stress. Newly identified lncRNA ECONEXIN regulates the topoisomerase 2 alpha (TOP2A) expression via upregulation of certain miRNA, which controls topological states of DNA by transient breakage and subsequent rejoining of DNA strands, in glioma cells. Another lncRNA TUG1 directly interacted with replication protein A (RPA), particularly under nucleotides depleted condition, and regulated its function. Depletion of TUG1 induced robust accumulation of double strand breaks, which were predominant in cancer cells with chromosomal instability, resulting in inhibition of cell proliferation and induction of apoptotic cell death. Our data demonstrated that a subset of lncRNAs play a critical role in regulation of DNA replication in cancer cells and provide a strong rationale whereby targeting such lncRNAs might be an effective novel strategy for cancer treatment.