PXD059843-1

PXD059843 is an original dataset announced via ProteomeXchange.

Title	DNA2 and MSH2 activities collectively mediate environmental chemical compound stabilized G4 for efficient telomere replication
Description	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, similar to 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 fragility, especially in cells deficient in DNA2 or MSH2.
HostingRepository	PRIDE
AnnounceDate	2025-08-07
AnnouncementXML	Submission_2025-08-07_12:37:15.290.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD059843
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Tingting Zhou
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-15 16:27:04	ID requested
⏵ 1	2025-08-07 12:37:15	announced

10.6019/PXD059843;

submitter keyword: G-quadruplex, MSH2, DNA2, telomere

Binghui Shen
contact affiliation	Departments of Cancer Genetics and Epigenetics Beckman Research Institute, City of Hope, Duarte, CA 91007, USA
contact email	bshen@coh.org
lab head
Tingting Zhou
contact affiliation	Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope
contact email	tizhou@coh.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/08/PXD059843

PRIDE project URI

• PRIDE
  1. PXD059843
     1. Label: PRIDE project
     2. Name: DNA2 and MSH2 activities collectively mediate environmental chemical compound stabilized G4 for efficient telomere replication