DDX41 coordinates RNA splicing and transcriptional elongation to prevent DNA replication stress in hematopoietic cells

• DOI: 10.1038/s41375-022-01708-9
• Publication Date: 2022-10-14T01:02:49Z
• Authors: Satoru Shinriki; Mayumi Hirayama; Akiko Nagamachi; Akihiko Yokoyama; Takeshi Kawamura; Akinori Kanai; Hidehiko Kawai; Junichi Iwakiri; Rin Liu; Manabu Maeshiro; Saruul Tungalag; Masayoshi Tasaki; Mitsuharu Ueda; Kazuhito Tomizawa; Naoyuki Kataoka; Takashi Ideue; Yutaka Suzuki; Kiyoshi Asai; Tokio Tani; Toshiya Inaba; Hirotaka Matsui
• Keywords: DNA Replication; 0301 basic medicine; 0303 health sciences; 03 medical and health sciences; RNA Splicing; Mutation; RNA Splice Sites; Article; Cell Line

AbstractMyeloid malignancies withDDX41mutations are often associated with bone marrow failure and cytopenia before overt disease manifestation. However, the mechanisms underlying these specific conditions remain elusive. Here, we demonstrate that loss of DDX41 function impairs efficient RNA splicing, resulting in DNA replication stress with excess R-loop formation. Mechanistically, DDX41 binds to the 5′ splice site (5′SS) of coding RNA and coordinates RNA splicing and transcriptional elongation; loss of DDX41 prevents splicing-coupled transient pausing of RNA polymerase II at 5ʹSS, causing aberrant R-loop formation and transcription-replication collisions. Although the degree of DNA replication stress acquired in S phase is small, cells undergo mitosis with under-replicated DNA being remained, resulting in micronuclei formation and significant DNA damage, thus leading to impaired cell proliferation and genomic instability. These processes may be responsible for disease phenotypes associated withDDX41mutations.