Höfundar:
Birta D. Jónsdóttir, Karen Kristjánsdóttir, Linda Viðarsdóttir, Stefán Sigurðsson
Of the many forms of damage cells endure every day DNA double-strand breaks (DSBs) are thought to be the most serious. DSBs can lead to cell death or chromosomal translocations if left unrepaired or incorrectly repaired. Our findings indicate that ALKBH3 and FTO, members of the alkylation-repair family (AlkB) with known mRNA demethylase activity, influence RNF168, a key regulator of DNA DSB repair, and therefore, play an important role in DNA DSB repair. By removing methylation marks from the RNF168-transcript, these enzymes affect RNF168 mRNA export; FTO removes N6-methyladenosine (m6A), and ALKBH3 removes N1-methyladenosine (m1A) and suggests a novel form of epitranscriptomic regulation of RNF168.
By performing DNA-DSB repair assays and survival assays in ALKBH3 and FTO knockout cell lines and siRNA knockdown treatment, our research has shown less effective DNA-DSB repair and increased vulnerability to various cancer drug treatments. This can be explained by decreased recruitment of essential DNA-DSB repair proteins to the site of DNA damage which ultimately affects DNA repair. This data indicates the importance of ALKBH3 and FTO for survival following the treatment of DNA DSB-inducing agents.
This novel crosstalk between the two DNA repair pathways, DNA alkylation repair and DNA-DSB repair, might give further insight into DNA repair dynamics. Due to both a lack of alkylation repair and defective DNA DSP repair, the deficiency of ALKBH3 and FTO may be used as potential markers for cancer treatment response or as potential treatment targets.
