G-quadruplex stabilization provokes DNA breaks in human PKD1, revealing a second hit mechanism for ADPKD

Agata M. Parsons, Seth Byrne, Jesse Kooistra, John Dewey, Aaron L. Zebolsky, Gloria Alvarado, Gerrit J. Bouma, Gregory B. Vanden Heuvel and Erik D. Larson ()
Additional contact information
Agata M. Parsons: Western Michigan University Homer Stryker MD School of Medicine
Seth Byrne: Western Michigan University Homer Stryker MD School of Medicine
Jesse Kooistra: Western Michigan University Homer Stryker MD School of Medicine
John Dewey: Western Michigan University Homer Stryker MD School of Medicine
Aaron L. Zebolsky: Western Michigan University Homer Stryker MD School of Medicine
Gloria Alvarado: Western Michigan University Homer Stryker MD School of Medicine
Gerrit J. Bouma: Western Michigan University Homer Stryker MD School of Medicine
Gregory B. Vanden Heuvel: Western Michigan University Homer Stryker MD School of Medicine
Erik D. Larson: Western Michigan University Homer Stryker MD School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract The “secondhit” pathway is responsible for biallelic inactivation of many tumor suppressors, where a pathogenic germline allele is joined by somatic mutation of the remaining functional allele. The mechanisms are unresolved, but the human PKD1 tumor suppressor is a good experimental model for identifying the molecular determinants. Inactivation of PKD1 results in autosomal dominant polycystic kidney disease, a very common disorder characterized by the accumulation of fluid-filled cysts and end-stage renal disease. Since human PKD1 follows second hit and mouse Pkd1 heterozygotes do not, we reasoned that there is likely a molecular difference that explains the elevated mutagenesis of the human gene. Here we demonstrate that guanine quadruplex DNA structures are abundant throughout human, but not mouse, PKD1 where they activate the DNA damage response. Our results suggest that guanine quadruplex DNAs provoke DNA breaks in PKD1, providing a potential mechanism for cystogenesis in autosomal dominant polycystic kidney disease specifically and for the inactivation of guanine quadruplex-rich tumor suppressors generally.

Date: 2025
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-55684-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55684-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-55684-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().