Journal
LEUKEMIA
Volume 36, Issue 11, Pages 2605-2620Publisher
SPRINGERNATURE
DOI: 10.1038/s41375-022-01708-9
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Funding
- Japanese Society for the Promotion of Science [16H06279, 21K08419, 18K08334, 22K17187, 22K10195]
- Uehara Memorial Foundation
- Friends of Leukemia Research Fund
- Kanae Foundation for the Promotion of Medical Science
- Senshin Medical Research Foundation
- Takeda Science Foundation
- Foundation for Promotion of Cancer Research
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Loss of DDX41 function impairs RNA splicing and leads to DNA replication stress and R-loop formation. DDX41 binds to the splice site of coding RNA, coordinating RNA splicing and transcriptional elongation. Its loss causes splicing impairment and aberrant R-loop formation. These processes may be responsible for disease phenotypes associated with DDX41 mutations.
Myeloid malignancies with DDX41 mutations 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 5MODIFIER LETTER PRIMESS, 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 with DDX41 mutations.
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