G-quadruplex stabilization provokes DNA breaks in human PKD1, revealing a second hit mechanism for ADPKD
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 f...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55684-y |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |