A novel lncRNA YIL163C enhances genomic stability and antifungal resistance via the DNA damage response in Saccharomyces cerevisiae

Xueting Wang ^1,2 XUEMEI LI ¹ Duoyun Li ³ Yiying Zhang ³ Bing Bai ³ Bao Chai ³ Zewen Wen ^3*

• ¹ Department of Dermatology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
• ² Guangdong Provincial Key Laboratory of Vegetable New Technology Research, Guangdong Academy of Agricultural Sciences, Guangzhou, Guangdong Province, China
• ³ Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China

Long non-coding RNAs (lncRNAs) have recently emerged as critical regulators in diverse cellular processes, including the DNA damage response (DDR). The role of lncRNAs in maintaining genomic integrity under stress conditions is an expanding area of study. In Saccharomyces cerevisiae, DDR plays a pivotal role in cellular responses to DNA damage, particularly through key signaling proteins such as Mec1 and Rad53. However, the involvement of lncRNAs in DDR pathways, especially under conditions of replication stress, remains largely unexplored. In this study, a novel lncRNA termed YIL163C, which contributes to promoting cell survival and preserving genomic stability in yeast was identified. Genetic suppressor screening revealed that overexpressing YIL163C rescues the lethality in mec1Δ sml1Δ and rad53Δ sml1Δ mutants exposed to DNA damage. Proteomic and phosphoproteomic analyses showed that YIL163C modulates protein abundance and phosphorylation states, particularly in pathways related to DNA replication, ER stress response, and ribosome biogenesis, thereby enhancing the cell's capacity to withstand hydroxyurea (HU)-induced stress. Additionally, YIL163C was found to regulate antifungal drug tolerance, reducing sensitivity to 5-fluorocytosine. Our study reveals YIL163C as a lncRNA involved in DDR, possibly acting as a downstream effector of the Mec1-Rad53 signaling pathway. This study provides new insights into the regulatory mechanisms of lncRNAs in DDR, with broader implications for antifungal therapy and genomic stability research, emphasizing the role of lncRNAs in stress responses beyond traditional protein-centric mechanisms.