Ye Jin Lee, Seo Yun Lee, Soomi Kim, Soo-Hyun Kim, Soo Hyeon Lee, Sungho Park, Jae Jin Kim, Dong-Wook Kim, Hongtae Kim
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引用次数: 0
摘要
众所周知,由 BCR::ABL1 融合基因引起的慢性髓性白血病(CML)会通过改变基因的表达来调控疾病的进展。然而,这些变化的分子机制在很大程度上还不为人知。在这项研究中,我们发现 RNA Exonuclease 5 (REXO5/LOC81691) 是慢性髓性白血病(CML)患者中 mRNA 表达水平升高的新基因。此外,我们利用 REXO5 基因敲除(KO)K562 细胞系,揭示了 REXO5 在 DNA 损伤应答(DDR)中的新作用。与野生型(WT)细胞相比,REXO5 KO细胞显示出R环的积累和DNA损伤的增加。我们证实,REXO5通过其RNA识别基序(RRM)转运到DNA损伤位点,并选择性地与R环结合。有趣的是,我们发现 REXO5 通过利用其外切酶结构域降解 R 环内的 mRNA 来调节 R 环水平。REXO5 KO显示了ATR-CHK1的激活。总之,我们证明了 REXO5 利用其外切酶结构域在 R 环的生理调控中发挥着关键作用。这些发现可能为了解 REXO5 表达变化如何导致 CML 发病提供了新的见解。
REXO5 promotes genomic integrity through regulating R-loop using its exonuclease activity
Chronic myeloid leukemia (CML), caused by BCR::ABL1 fusion gene, is known to regulate disease progression by altering the expression of genes. However, the molecular mechanisms underlying these changes are largely unknown. In this study, we identified RNA Exonuclease 5 (REXO5/LOC81691) as a novel gene with elevated mRNA expression levels in chronic myeloid leukemia (CML) patients. Additionally, using the REXO5 knockout (KO) K562 cell lines, we revealed a novel role for REXO5 in the DNA damage response (DDR). Compared to wild-type (WT) cells, REXO5 KO cells showed an accumulation of R-loops and increased DNA damage. We demonstrated that REXO5 translocates to sites of DNA damage through its RNA recognition motif (RRM) and selectively binds to R loops. Interestingly, we identified that REXO5 regulates R-loop levels by degrading mRNA within R-loop using its exonuclease domain. REXO5 KO showed ATR-CHK1 activation. Collectively, we demonstrated that REXO5 plays a key role in the physiological control of R-loops using its exonuclease domain. These findings may provide novel insights into how REXO5 expression changes contribute to CML pathogenesis.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues