lncRNA-ZFAS1, an emerging gate-keeper in DNA damage-dependent transcriptional regulation [lncRNA-seq]

The hereditary information encoded in DNA sequence is intrinsically susceptible to alterations, being continually threatened by a variety of genotoxic perturbations. To safeguard the stability of the genome, eukaryotic cells have evolved a set of sophisticated surveillance system that controls several aspects of the cellular response, including the detection of DNA lesions, a temporary cell cycle arrest, regulation of transcription, and the repair of the damaged DNA. However, it is still poorly understood how the DNA damage checkpoints and stalled RNAPII molecules convert a very limited amount of molecular-level information (even a single DNA lesion) in the context of an otherwise genome into regulation that halts and resumes the cell-cycle engine in a coordinated way. In this study, we reveal a map of extensive lncRNA transcription during DDR by using synchronized cells, leading to the unexpected identification of a poorly characterized mammalian lncRNA-ZFAS1. We describe that ZFAS1 functions as a key player of cellular response to DNA damage in both human and rodent cells by fine tuning RNAPII kinetics, suggesting a lncRNA-dependent transcriptional regulatory axis that maintains genomic stability upon DNA damage in mammalian cells. To illustrate the transcriptome map for both mRNAs and lncRNAs during DNA damage response, we synchronized human fibroblasts MRC5_VA at G1/S block and UV irradiated prior to release from the arrested cell cycle phase. We then performed gene expression profiling analysis using data obtained from RNA-seq of 14 samples, including undisturbed (6 samples) and UV-irradiated (8 samples) cell lines at the indicated time intervals after release from G1/S block.