Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2021
Erindi/veggspjald / Talk/poster E28
Höfundar / Authors: Stefán Þ. Sigurðsson (1), Karen Kristjánsdóttir (1), Þorkell Guðjónsson
Starfsvettvangur / Affiliations: 1. Univeristy of Iceland, 2. University of Copenhagen
Kynnir / Presenter: Karen Kristjánsdóttir
DNA double strand breaks (DSB) are thought the most cytotoxic from of DNA damage. Unrepaired or incorrectly repaired DSBs can result in cell death or cause chromosomal translocation, an early step in the aetiology of carcinogenesis. ALKBH3 & FTO are dioxygenases with well-described functions in DNA/RNA alkylation repair with known mRNA demethylase activity. Previous work published by our laboratory, revealed that ALKBH3 is promoter hyper-methylated in ~20% of breast cancers. This form of epigenetic regulation reduces ALKBH3 expression and resulted in reduced survival. Exploring the function of silencing ALKBH3&FTO revealed knockdown of these genes caused nuclear retention of RNF168mRNA and reduced RNF168-protein expression, a key protein in DNA DSB repair, which caused decreased recruitment of crucial DNA-DSB repair proteins to the site of DNA damage affecting DNA repair. Further research revealed RNF168mRNA contains both m6A & m1A methylation and which ALKBH3 & FTO are responsible for removing. These results suggest a novel form of epitranscriptomic regulation of RNF168 mRNA export by removing mRNA methylations and subsequently a new form of regulation of DNA-DSB repair pathway. Hence, lack of FTO or ALKBH3 might prove useful as a potential marker of cancer treatment response due to both their well-established role in alkylation damage repair and due to this newly established role in DNA DSB repair, highlighting the potential clinical benefits of this project.