AND-1 is a critical regulator of R-loop dynamics and a target to overcome endocrine resistance

Authors

Zhuqing Li, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Yihan Peng, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Huai-Chin Chiang, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Yanjun Gao, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Chen Chu, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Yi Zhang, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Muhammad Jameel Mughal, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Chengyu Liu, The Transgenic Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Rong Li, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Huadong Pei, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Wenge Zhu, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Document Type

Journal Article

Publication Date

8-8-2025

Journal

Science advances

Volume

11

Issue

32

DOI

10.1126/sciadv.adv2453

Abstract

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 ESR1 expression by disrupting R-loop regulation at the enhancer region of the ESR1 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.

APA Citation

Li, Zhuqing; Peng, Yihan; Chiang, Huai-Chin; Gao, Yanjun; Chu, Chen; Zhang, Yi; Mughal, Muhammad Jameel; Liu, Chengyu; Li, Rong; Pei, Huadong; and Zhu, Wenge, "AND-1 is a critical regulator of R-loop dynamics and a target to overcome endocrine resistance" (2025). GW Authored Works. Paper 7800.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7800

Department

Biochemistry and Molecular Medicine