Li Zhuqing, Peng Yihan, Chiang Huai-Chin, Gao Yanjun, Chu Chen, Zhang Yi, Mughal Muhammad Jameel, Liu Chengyu, Li Rong, Pei Huadong, Zhu Wenge
Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
GW Cancer Center, George Washington University, Washington, DC, USA.
Sci Adv. 2025 Aug 8;11(32):eadv2453. doi: 10.1126/sciadv.adv2453.
R-loops are three-stranded DNA/RNA hybrids that are essential for various cellular pathways. However, when dysregulated, they lead to genomic instability and numerous human diseases. R-loops are tightly regulated, with RNase H1 acting as a key enzyme responsible for resolving DNA/RNA hybrids. Here, we identify the DNA-binding protein AND-1 as an essential factor in R-loop regulation through directly binding to R-loop structures, where it enhances the recruitment of RNase H1 and stimulates its endonuclease activity. We also provide in vivo evidence that R-loop accumulation occurs in the mammary gland tissue of AND-1-deficient mice. Furthermore, we demonstrate that inhibition of AND-1 decreases expression by disrupting R-loop regulation at the enhancer region of the gene in estrogen receptor-positive (ER) breast cancer cells, thereby overcoming resistance to aromatase inhibitors. Collectively, our findings reveal a mechanism by which AND-1 modulates R-loop dynamics and present a promising therapeutic strategy to combat endocrine resistance in breast cancer.
R环是三链DNA/RNA杂交体，对各种细胞通路至关重要。然而，当失调时，它们会导致基因组不稳定和多种人类疾病。R环受到严格调控，核糖核酸酶H1作为负责分解DNA/RNA杂交体的关键酶。在这里，我们确定DNA结合蛋白AND-1是R环调控的一个重要因素，它通过直接结合R环结构，增强核糖核酸酶H1的募集并刺激其内切核酸酶活性。我们还提供了体内证据，证明在AND-1缺陷小鼠的乳腺组织中发生了R环积累。此外，我们证明抑制AND-1会通过破坏雌激素受体阳性（ER）乳腺癌细胞中该基因增强子区域的R环调控来降低 表达，从而克服对芳香化酶抑制剂的耐药性。总的来说，我们的发现揭示了AND-1调节R环动态的机制，并提出了一种有前景的治疗策略来对抗乳腺癌中的内分泌耐药性。
