202203Hirayama

研究発表を行った学会；第44回日本分子生物学会年会
2021年12月1-3日　（横浜市/オンライン ハイブリッド開催）
タイトル； DDX41機能抑制はスプライシング異常を引き起こしR-loop依存性DNAダメージを誘導する.
Loss of DDX41 function induces RNA splicing disability that results in R-loop-associated DNA damage.
発表者；平山　真弓氏
（熊本大学　大学院生命科学研究部　臨床病態解析学講座）
要旨；
DEAD-box helicase 41 (DDX41) is one of the highly conserved DEAD-box type RNA helicases in human, and it plays multiple roles on RNA processing including transcription, pre-mRNA splicing, protein translation and ribosome biogenesis. The mutation of DDX41 gene is found in 1-2% of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) patients, however the pathogenesis is not elucidated. Here, we investigated the underlying mechanism by which DDX41 dysfunction causes leukemogenesis. We found that DDX41 knockdown cells showed growth defect and mitotic abnormality, along with the accumulation of R-loop, a three-stranded structure containing DNA: RNA-hybrid and a single DNA strand formed during transcription, and ATR-Chk1-mediated DNA damage response. Furthermore, our RNA-seq analyses showed that DDX41 inhibition caused altered RNA splicing in a manner different from that in cells expressing mutant SRSF2. The defect in RNA splicing caused impaired transcriptional elongation, possibly due to a loss of cooperation between the two systems. Our data suggest that DDX41 controls myeloid progenitors by regulating RNA splicing as well as reducing DNA damage and R-loop accumulation.