김유진 (가톨릭대학교)

한빛사논문

조회232

가톨릭대학교

Leukemia, Mar 21 2024, | https://doi.org/10.1038/s41375-024-02228-4 Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation

Won Chan Hwang^1,8, Kibeom Park^1,8, Silvia Park^2,3,8, Na Young Cheon^1,8, Ja Yil Lee^1,8, Taejoo Hwang⁴, Semin Lee⁴, Jong-Mi Lee^5,6, Min Kyung Ju¹, Joo Rak Lee¹, Yong-Rim Kwon³, Woo-Lam Jo^5,7, Myungshin Kim^5,6, Yoo-Jin Kim^2,3and Hongtae Kim¹

¹Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.

²Department of Hematology, Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

³Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁴Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan, Korea.

⁵Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁶Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁷Department of Orthopaedic Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁸These authors contributed equally: Won Chan Hwang, Kibeom Park, Silvia Park, Na Young Cheon, Ja Yil Lee.

Corresponding authors : Correspondence to Myungshin Kim, Yoo-Jin Kim or Hongtae Kim.

Abstract

DEAD box helicase 41 (DDX41) mutations are the most prevalent predisposition to familial myelodysplastic syndrome (MDS). However, the precise roles of these variants in the pathogenesis of MDS have yet to be elucidated. Here, we discovered a novel mechanism by which DDX41 contributes to R-loop-induced DNA damage responses (DDR) in cooperation with the m6A-METTL complex (MAC) and YTHDC1 using DDX41 knockout (KO) and DDX41 knock-in (KI, R525H, Y259C) cell lines as well as primary samples from MDS patients. Compared to wild type (WT), DDX41 KO and KI led to increased levels of m6A RNA methylated R-loop. Interestingly, we found that DDX41 regulates m6A/R-loop levels by interacting with MAC components. Further, DDX41 promoted the recruitment of YTHDC1 to R-loops by promoting the binding between METTL3 and YTHDC1, which was dysregulated in DDX41-deficient cells, contributing to genomic instability. Collectively, we demonstrated that DDX41 plays a key role in the physiological control of R-loops in cooperation with MAC and YTHDC1. These findings provide novel insights into how defects in DDX41 influence MDS pathogenesis and suggest potential therapeutic targets for the treatment of MDS.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-25)
연구진국내 연구진
분야 의약학 > 종양의학

댓글 작성 로그인

CV 열람하기

연락처 보기