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

被引：23

作者：

Shinriki, Satoru ^{[1
]}

Hirayama, Mayumi ^{[1
,2
]}

Nagamachi, Akiko ^{[3
,4
]}

Yokoyama, Akihiko ^{[5
]}

Kawamura, Takeshi ^{[6
]}

Kanai, Akinori ^{[7
]}

Kawai, Hidehiko ^{[8
]}

Iwakiri, Junichi ^{[9
]}

Liu, Rin ^{[1
,10
]}

Maeshiro, Manabu ^{[1
,10
]}

Tungalag, Saruul ^{[1
]}

Tasaki, Masayoshi ^{[11
]}

Ueda, Mitsuharu ^{[12
]}

Tomizawa, Kazuhito ^{[13
]}

Kataoka, Naoyuki ^{[14
]}

Ideue, Takashi ^{[15
]}

Suzuki, Yutaka ^{[7
]}

Asai, Kiyoshi ^{[9
]}

Tani, Tokio ^{[15
]}

Inaba, Toshiya ^{[3
,4
]}

Matsui, Hirotaka ^{[1
]}

机构：

[1] Kumamoto Univ, Fac Life Sci, Dept Mol Lab Med, Kumamoto, Japan

[2] Kumamoto Univ, Int Res Ctr Med Sci, Lab Transcript Regulat Leukemogenesis, Kumamoto, Japan

[3] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Hiroshima, Japan

[4] Hiroshima Univ, Res Inst Radiat Biol & Med, Leukemia Program Project, Hiroshima, Japan

[5] Natl Canc Ctr, Tsuruoka Metabol Lab, Yamagata, Japan

[6] Univ Tokyo, Isotope Sci Ctr, Tokyo, Japan

[7] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Lab Syst Genom, Chiba, Japan

[8] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Nucle Acids Biochem, Hiroshima, Japan

[9] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Lab Genome Informat, Chiba, Japan

[10] Kumamoto Univ, Fac Life Sci, Dept Oral & Maxillofacial Surg, Kumamoto, Japan

[11] Kumamoto Univ, Fac Life Sci, Dept Biomed Lab Sci, Kumamoto, Japan

[12] Kumamoto Univ, Fac Life Sci, Dept Neurol, Kumamoto, Japan

[13] Kumamoto Univ, Fac Life Sci, Dept Mol Physiol, Kumamoto, Japan

[14] Univ Tokyo, Grad Sch Agr & Life Sci, Dept Anim Resource Sci, Lab Cellular Biochem, Tokyo, Japan

[15] Kumamoto Univ, Fac Adv Sci & Technol, Dept Biol Sci, Kumamoto, Japan

来源：

LEUKEMIA | 2022年 / 36卷 / 11期

关键词：

C-TERMINAL DOMAIN; POLYMERASE-II; R-LOOPS; ROBUST; PHOSPHORYLATION; SPLICEOSOME; ACTIVATION; EXPRESSION; MUTATIONS; LANDSCAPE;

D O I：

10.1038/s41375-022-01708-9

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2605 / 2620

页数：16

共 68 条

[1] Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms [J].