DNA2 and MSH2 cooperatively repair stabilized G4 and allow efficient telomere replication

作者：Anthony P. Fernandez, Tingting Zhou, Yi Lei, Nian Liu, R. Steven Esworthy, Changxian Shen, Helen Liu, Jessica D. Hess, Hang Yuan, Guojun Shi, Mian Zhou, Lei Shen, Sufang Zhang, Settapong T Kosiyatrakul, Vikas Gaur, Joshua A. Sommers, Nityanand Srivastava, Winfried Edelmann, Guo‐Min Li, Robert M. Brosh, Weihang Chai, Marietta Lee, Dong Zhang, Carl L. Schildkraut, Li Zheng, Binghui Shen · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63505-z · 被引用次数：6 · 研究领域：DNA and Nucleic Acid Chemistry、Advanced biosensing and bioanalysis techniques、DNA Repair Mechanisms

G-quadruplexes (G4s) are widely existing stable DNA secondary structures in mammalian cells. A long-standing hypothesis is that timely resolution of G4s is needed for efficient and faithful DNA replication. In vitro, G4s may be unwound by helicases or alternatively resolved via DNA2 nuclease mediated G4 cleavage. However, little is known about the biological significance and regulatory mechanism of the DNA2-mediated G4 removal pathway. Here, we report that DNA2 deficiency or its chemical inhibition leads to a significant accumulation of G4s and stalled replication forks at telomeres, which is demonstrated by a high-resolution technology: Single molecular analysis of replicating DNA (SMARD). We further identify that the DNA repair complex MutSα (MSH2-MSH6) binds G4s and stimulates G4 resolution via DNA2-mediated G4 excision. MSH2 deficiency, like DNA2 deficiency or inhibition, causes G4 accumulation and defective telomere replication. Meanwhile, G4-stabilizing environmental compounds block G4 unwinding by helicases but not G4 cleavage by DNA2. Consequently, G4 stabilizers impair telomere replication and cause telomere instabilities, especially in cells deficient in DNA2 or MSH2.