DHX9 SUMOylation is required for the suppression of R-loop-associated genome instability

Bing-Ze Yang, Mei-Yin Liu, Kuan-Lin Chiu, Yuh-Ling Chien, Ching-An Cheng, Yu-Lin Chen, Li-Yu Tsui, Keng-Ru Lin, Hsueh-Ping Catherine Chu and Ching-Shyi Peter Wu ()
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Bing-Ze Yang: College of Medicine, National Taiwan University
Mei-Yin Liu: College of Medicine, National Taiwan University
Kuan-Lin Chiu: National Taiwan University
Yuh-Ling Chien: College of Medicine, National Taiwan University
Ching-An Cheng: College of Medicine, National Taiwan University
Yu-Lin Chen: College of Medicine, National Taiwan University
Li-Yu Tsui: College of Medicine, National Taiwan University
Keng-Ru Lin: College of Medicine, National Taiwan University
Hsueh-Ping Catherine Chu: National Taiwan University
Ching-Shyi Peter Wu: College of Medicine, National Taiwan University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract RNA helicase DHX9 is essential for genome stability by resolving aberrant R-loops. However, its regulatory mechanisms remain unclear. Here we show that SUMOylation at lysine 120 (K120) is crucial for DHX9 function. Preventing SUMOylation at K120 leads to R-loop dysregulation, increased DNA damage, and cell death. Cells expressing DHX9 K120R mutant which cannot be SUMOylated are more sensitive to genotoxic agents and this sensitivity is mitigated by RNase H overexpression. Unlike the mutant, wild-type DHX9 interacts with R-loop-associated proteins such as PARP1 and DDX21 via SUMO-interacting motifs. Fusion of SUMO2 to the DHX9 K120R mutant enhances its association with these proteins, reduces R-loop accumulation, and alleviates survival defects of DHX9 K120R. Our findings highlight the critical role of DHX9 SUMOylation in maintaining genome stability by regulating protein interactions necessary for R-loop balance.

Date: 2024
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DOI: 10.1038/s41467-024-50428-4

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