Numerous long noncoding RNAs (lncRNAs) are generated in response to external stimuli, but the scope and functions of such activity are not known. Here, this study provides insight into how the transcription of lncRNAs is connected to DNA damage response by identifying the lncRNA ZFAS1, which is required for cell cycle arrest, transcription regulation, and DNA repair. Mechanistically, ZFAS1 facilitates dynamic changes in hyperphosphorylated forms of the large subunit of RNA polymerase II (RNAPII) around transcription initiation sites by directly targeting the regulated genes. It is shown that extensive transcription shutdown and concomitant stimulated engagement of RNAPII-Ser2P are crucial for repair and cell survival upon genotoxic stress. Finally, ZFAS1 knockout in mice dampened nucleotide excision repair (NER) and led to kidney dysplasia. Overall, the findings extend the understanding of lncRNAs in DNA damage repair (DDR) and imply a protective role of lncRNA against DDR-deficient developmental disorders.
Keywords: IncRNA‐ZFAS1; UV‐C irradiation; nucleotide excision repair; transcription regulation.
© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.