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.

慢性粒细胞白血病 (CML) 由 BCR::ABL1 融合基因引起，已知可通过改变基因表达来调节疾病进展。然而，这些变化背后的分子机制在很大程度上尚不清楚。在这项研究中，我们发现 RNA 核酸外切酶 5 ( REXO5/LOC81691 ) 是一种新基因，在慢性粒细胞白血病 (CML) 患者中 mRNA 表达水平升高。此外，使用REXO5敲除 (KO) K562 细胞系，我们揭示了 REXO5 在 DNA 损伤反应 (DDR) 中的新作用。与野生型 (WT) 细胞相比， REXO5 KO 细胞表现出 R 环积累和 DNA 损伤增加。我们证明了 REXO5 通过其 RNA 识别基序 (RRM) 易位到 DNA 损伤位点，并选择性地与 R 环结合。有趣的是，我们发现 REXO5 通过使用其核酸外切酶结构域降解 R 环内的 mRNA 来调节 R 环水平。 REXO5 KO 显示 ATR-CHK1 激活。总的来说，我们证明了 REXO5 利用其核酸外切酶结构域在 R 环的生理控制中发挥着关键作用。这些发现可能为REXO5表达变化如何促进 CML 发病机制提供新的见解。