Oral Presentation Australasian RNA Biology and Biotechnology Association 2024 Conference

The RNA demethylase FTO suppresses DNA repair by inhibiting PARP1 (112869)

Jocelyn Widagdo 1 , Tianyi Zhu 2 , Jing Zhi Anson Tan 2 , Lingrui Zhang 2 , He Huang 2 , Sooraj S Das 2 , Flora Cheng 3 , Pranesh Padmanabhan 2 , Mathew J Jones 4 , Mihwa Lee 5 , Albert Lee 3 , Victor Anggono 2
  1. University of Queensland, St Lucia, QLD, Australia
  2. Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
  3. Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine Health and Human Sciences, Macquarie University, Sydney, NSW
  4. Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD
  5. Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC

N6-methyladenosine (m6A) is an abundant RNA modification in eukaryotic RNAs that affects multiple forms of RNA processing, gene expression, and most recently, the DNA damage response (DDR). In DDR, m6A is rapidly induced at the site of DNA damage, and this accumulation is important for efficient DNA repair. However, molecular details of the downstream m6A-signalling in DDR are not well understood. Our study aims to uncover the role of the m6A-demethylase protein FTO (Fat mass and obesity-associated protein) by performing an unbiased screen of endogenous FTO-proximal interactome. We identified a direct interaction of FTO with the DNA damage sensor protein PARP1 (poly-ADP-ribose polymerase 1), which dissociates upon ultraviolet (UV) stimulation. FTO inhibits PARP1 catalytic activity and controls its clustering in the nucleolus. Loss of FTO enhances PARP1 enzymatic activity and the rate of PARP1 recruitment to DNA damage sites, thereby accelerating DNA repair and promoting cell survival. Interestingly, the RNA demethylase activity of FTO is not required for its interaction with PARP1 nor the effect on PARylation activity following UV exposure in cells. We conclude that FTO is an endogenous negative regulator of PARP1 and the UV-induced DNA damage response in cells.