Regulation of Multiple Cellular Processes by the Long Noncoding RNA LINC00662
- Author(s): Schrier, Jacob
- Advisor(s): Liu, Xuan
- et al.
Throughout the past several decades it has become increasingly apparent that a large proportion of the human genome is transcribed, while only a small fraction (~2%) codes for protein. Among the non-coding transcriptome is a class of RNA termed long noncoding RNAs. Although recent estimates have suggested close to 20,000 potentially functional long noncoding RNAs within the human genome, the functions and mechanisms of these transcripts remain largely unexplored. In the studies presented here, we demonstrate novel functions and molecular mechanisms for the long noncoding RNA, LINC00662, in 2 different cellular processes: DNA damage repair and cancer cell migration. We found that in response to UV irradiation, LINC00662 is up-regulated through a splicing mechanism dependent upon hnRNP C binding to an Alu sequence within LINC00662 exon 3. Surprisingly, we also found that this UV-induced splicing mechanism is likely regulated by N6-methyladenosine (m6A) modification. We provide evidence that LINC00662 enhances non-homologous end joining through interaction with Ku70 and Ku80, leading to more efficient DNA damage repair. We also found that loss of LINC00662 alters cell morphology and migratory potential for cancer cells, likely through regulation of genes involved in extracellular matrix organization and eukaryotic translation elongation. Finally, we show that LINC00662 is often overexpressed in several cancers, and that altered LINC00662 expression is correlated with clinical outcomes for select cancers. Together, these studies further our understanding of the diverse regulatory roles for long noncoding RNAs in complex cellular processes, and implicate LINC00662 as a functionally significant long noncoding RNA for human health and disease.