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

Anthony Fernandez, Tingting Zhou, Yi Lei, Nian Liu, Steven Esworthy, Changxian Shen, Helen Liu, Jessica D. Hess, Hang Yuan, Guojun Shi, Mian Zhou, Lei Shen, Sufang Zhang, Settapong Kosiyatrakul, Vikas Gaur, Joshua A. Sommers, Nityanand Srivastava, Winfried Edelmann, Guo-Min Li, Robert M. Brosh, Weihang Chai, Marietta Y. W. T. Lee, Dong Zhang, Carl Schildkraut, Li Zheng () and Binghui Shen ()
Additional contact information
Anthony Fernandez: City of Hope
Tingting Zhou: City of Hope
Yi Lei: City of Hope
Nian Liu: City of Hope
Steven Esworthy: City of Hope
Changxian Shen: City of Hope
Helen Liu: City of Hope
Jessica D. Hess: City of Hope
Hang Yuan: City of Hope
Guojun Shi: City of Hope
Mian Zhou: City of Hope
Lei Shen: City of Hope
Sufang Zhang: New York Medical College
Settapong Kosiyatrakul: Department of Cell Biology, Albert Einstein College of Medicine
Vikas Gaur: Rosalind Franklin University of Medicine and Science
Joshua A. Sommers: National Institute on Aging
Nityanand Srivastava: Albert Einstein College of Medicine
Winfried Edelmann: Albert Einstein College of Medicine
Guo-Min Li: Chinese Institutes for Medical Research
Robert M. Brosh: National Institute on Aging
Weihang Chai: Rosalind Franklin University of Medicine and Science
Marietta Y. W. T. Lee: New York Medical College
Dong Zhang: New York Institute of Technology
Carl Schildkraut: Department of Cell Biology, Albert Einstein College of Medicine
Li Zheng: City of Hope
Binghui Shen: City of Hope

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63505-z

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