Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2025
Erindi/veggspjald / Talk/poster E58
Höfundar / Authors: Karen Kristjánsdóttir1,2, Þorkell Guðjónsson1,2,3, Stefan Thor Hermanowicz1,2, Arnar Ingi Vilhjálmsson1,2, Snærdís Ragnarsdóttir1,2, Drífa Hrund Guðmundssdóttir1,2, Birta Dröfn Jónsdóttir1,2, Erla Sveinbjörnsdóttir4, Linda Viðarsdóttir1,2, Stefán Sigurðsson1,2,
Starfsvettvangur / Affiliations: 1. Cancer Research Laboratory, Biomedical Center, Sturlugata 8, 101, Reykjavik, Iceland 2. Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland 3. Biotech Research & Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark 4. Department of Genetics and Molecular Medicine at University Hospital (Landspitali), Hringbraut, Reykjavik
Kynnir / Presenter: Stefán Sigurðsson
DNA double-strand breaks (DSBs) are among the most cytotoxic forms of DNA damage, and their faithful repair is essential to preserve genomic stability. ALKBH3 and FTO are dioxygenases best known for removing methylation from mRNA, ALKBH3 acting on N¹-methyladenosine (m¹A) and FTO on N⁶-methyladenosine (m⁶A). We previously showed that ALKBH3 is promoter-hypermethylated in ~20% of breast cancers, correlating with reduced expression and poor survival. Here, we uncover a novel role for ALKBH3 and FTO in regulating DNA DSB repair. Knockdown of either enzyme caused nuclear retention of RNF168 mRNA, a key factor in DSB signaling. Cells depleted of ALKBH3 or FTO displayed genomic instability and hypersensitivity to cancer drug treatment, comparable to RNF168-deficient cells. Moreover, loss of ALKBH3 or FTO impaired recruitment of DNA repair regulators including RIF1 and 53BP1 to DSB sites. Mechanistically, we show that RNF168 mRNA harbors both m¹A and m⁶A modifications, which are removed by ALKBH3 and FTO. Thus, these enzymes act as epitranscriptomic regulators of RNF168 protein expression. This reveals unexpected crosstalk between DNA alkylation repair enzymes and the DNA DSB repair pathway. Our findings identify ALKBH3 and FTO as novel regulators of the DSB response through mRNA demethylation. Deficiency in these enzymes may serve as a biomarker of defective repair and treatment sensitivity, and highlights a potential therapeutic vulnerability in cancer.