Noncoding RNAs in DNA Damage Response: Opportunities for Cancer Therapeutics.

Abstract

DNA repair machinery preserves genomic integrity, which is frequently challenged through endogenous and exogenous toxic insults, and any sort of repair machinery malfunctioning ultimately manifests in the form of several types of terrible human diseases such as cancers (Hoeijmakers, Nature 411(6835): 366-374, 2001). Noncoding RNAs (ncRNAs) are crucial players of DNA repair machinery in a cell and play a vital role in maintaining genomic stability, which is essential for its survival and normal functioning thus preventing tumorigenesis. To preserve the integrity of the genome, cells initiate a specific cellular response, recognized as DNA damage response (DDR), which includes several distinct DNA repair pathways. These repair pathways permit normal cells to repair DNA damage or induce apoptosis and cell cycle arrest in case the damage is irreparable. Disruption of these pathways in cancer leads to an increase in genomic instability and mutagenesis. Recently, emerging evidence suggests that ncRNAs play a critical role in the regulation of DDR. There is an extensive crosstalk between ncRNAs and the canonical DDR signaling pathway. DDR-induced expression of ncRNAs can provide a regulatory mechanism to accurately control the expression of DNA damage responsive genes in a spatio-temporal manner. DNA damage alters expression of a variety of ncRNAs at multiple levels including transcriptional regulation, post-transcriptional regulation, and RNA degradation and vice versa, wherein ncRNAs can directly regulate cellular processes involved in DDR by altering expression of their targeting genes, with a particular emphasis on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Relationship between the defects in the DDR and deregulation of related ncRNAs in human cancers is one of the established, which is growing stronger with the advent of high-throughput sequencing techniques such as next-generation sequencing. Understanding of the mechanisms that explain the association between ncRNAs and DDR/DNA repair pathways will definitely increase our understanding on human tumor biology and on different responses to diverse drugs. Different ncRNAs interact with distinct DDR components and are promising targets for improving the effects to overcome the resistance to conventional chemotherapeutic agents. In this chapter, we will focus the role of ncRNAs in the DNA damage, repair, and cancer.