DNA2 and MSH2 cooperatively repair stabilized G4 and allow efficient telomere replication
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.
Authors
- Dong Zhang (ORCID: https://orcid.org/0000-0002-4515-2070)
- Carl L. Schildkraut
- Marietta Y. W. T. Lee
- Binghui Shen (ORCID: https://orcid.org/0000-0002-4408-407X)
- Guojun Shi (ORCID: https://orcid.org/0000-0002-3098-6662)
- Settapong T Kosiyatrakul
- R. Steven Esworthy (ORCID: https://orcid.org/0000-0002-4111-3349)
- Tingting Zhou (ORCID: https://orcid.org/0000-0002-5760-736X)
- Robert M. Brosh (ORCID: https://orcid.org/0000-0003-2676-4327)
- Changxian Shen (ORCID: https://orcid.org/0000-0002-7668-7166)
- Joshua A. Sommers (ORCID: https://orcid.org/0000-0003-0859-6286)
- Hang Yuan (ORCID: https://orcid.org/0009-0000-2523-8144)
- Yi Lei (ORCID: https://orcid.org/0000-0002-6120-3464)
- Weihang Chai (ORCID: https://orcid.org/0000-0003-1206-2324)
- Nian Liu (ORCID: https://orcid.org/0000-0001-9393-239X)
- Nityanand Srivastava (ORCID: https://orcid.org/0000-0003-4118-2341)
- Jessica D. Hess (ORCID: https://orcid.org/0000-0001-8608-7458)
- Winfried Edelmann (ORCID: https://orcid.org/0000-0001-6958-9894)
- Li Zheng (ORCID: https://orcid.org/0000-0002-3744-185X)
- Anthony P. Fernandez (ORCID: https://orcid.org/0000-0003-4490-8427)
- Mian Zhou (ORCID: https://orcid.org/0000-0003-4226-6299)
- Vikas Gaur (ORCID: https://orcid.org/0000-0001-9050-7152)
- Lei Shen (ORCID: https://orcid.org/0000-0003-4040-8716)
- Sufang Zhang (ORCID: https://orcid.org/0000-0003-3883-023X)
- Helen Liu (ORCID: https://orcid.org/0000-0001-8290-270X)
- Guo‐Min Li (ORCID: https://orcid.org/0000-0002-9842-4578)
Institutions
- Albert Einstein College of Medicine (US)
- City Of Hope National Medical Center (US)
- University of California, Los Angeles (US)
- New York Medical College (US)
- Rosalind Franklin University of Medicine and Science (US)
- New York Institute of Technology (US)
- City of Hope (US)
- National Institute on Aging (US)
- Cancer Genetics (United States) (US)
- Beckman Research Institute
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41467-025-63505-z
- Citations
- 3
- Primary Topic
- DNA and Nucleic Acid Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 2.42