Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation

• Published in: Leukemia Vol. 38; no. 6; pp. 1353 - 1364
• Main Authors: Hwang, Won Chan, Park, Kibeom, Park, Silvia, Cheon, Na Young, Lee, Ja Yil, Hwang, Taejoo, Lee, Semin, Lee, Jong-Mi, Ju, Min Kyung, Lee, Joo Rak, Kwon, Yong-Rim, Jo, Woo-Lam, Kim, Myungshin, Kim, Yoo-Jin, Kim, Hongtae
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2024; Nature Publishing Group
• Subjects: 14; 14/1; 14/19; 38/1; 38/109; 38/70; 38/89; 45/23; 631/67/1990/1673; 631/67/69; 631/80/86; Binding; Cancer Research; Cell lines; Cooperation; Critical Care Medicine; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; DNA Damage; DNA helicase; Genomic instability; Hematology; Humans; Intensive; Internal Medicine; Medicine; Medicine & Public Health; Methyltransferases - genetics; Methyltransferases - metabolism; Mutation; Myelodysplastic syndrome; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - pathology; N6-methyladenosine; Neoplasms; Nerve Tissue Proteins; Oncology; Pathogenesis; Protein Binding; R-Loop Structures; R-loops; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism; Therapeutic targets
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-024-02228-4

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.