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

Author

Listed:
  • 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
    University of California at Los Angeles)

  • 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 Jr

    (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)

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.

Suggested Citation

  • 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 Kosiya, 2025. "DNA2 and MSH2 cooperatively repair stabilized G4 and allow efficient telomere replication," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63505-z
    DOI: 10.1038/s41467-025-63505-z
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    References listed on IDEAS

    as
    1. Massimo Lopes & Cecilia Cotta-Ramusino & Achille Pellicioli & Giordano Liberi & Paolo Plevani & Marco Muzi-Falconi & Carol S. Newlon & Marco Foiani, 2001. "The DNA replication checkpoint response stabilizes stalled replication forks," Nature, Nature, vol. 412(6846), pages 557-561, August.
    2. Gary N. Parkinson & Michael P. H. Lee & Stephen Neidle, 2002. "Crystal structure of parallel quadruplexes from human telomeric DNA," Nature, Nature, vol. 417(6891), pages 876-880, June.
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