Polymerase iota coordinates adaptation to replication stress in BRCA2-deficient mammary epithelial cells.

Authors

Kavya Vipparthi, Ariana Bellare, Resul Ozbilgic, Peter Bazeley, Nishtha Khanna, Fangfang Wang, Anand Bhushan, Liangqi Xie, Zahraa Al-Hilli, You-Wei Zhang, Mihriban Karaayvaz

Published in

iScience. Volume 29. Issue 11. Pages 117830. Nov 20, 2026. Epub Oct 09, 2026.

Abstract

BRCA2 deficiency induces chronic replication stress, yet how human mammary epithelial cells adapt before malignant transformation remains poorly understood. Here, we identify polymerase iota (Pol ι) as a context-dependent regulator of replication stress responses in BRCA2-deficient mammary epithelium. Single-cell transcriptomic analysis of preneoplastic breast epithelium from BRCA2 mutation carriers revealed enrichment of POLI-positive hormone-sensing cells, while BRCA2 depletion increased nuclear Pol ι in mammary epithelial models. Functionally, Pol ι promoted post-S-phase DNA synthesis specifically in BRCA2-deficient cells. Unexpectedly, POLI depletion reduced chromosomal instability and replication stress markers, while enhancing replication fork progression under replication stress. POLI depletion was also associated with expansion of a luminal-like epithelial population, linking altered replication stress processing to epithelial cell state remodeling. These findings identify Pol ι as a regulator of replication stress adaptation and provide a framework for understanding early cellular changes preceding BRCA2-associated breast tumorigenesis.

PMID:
42894850
Bibliographic data and abstract were imported from PubMed on 19 Oct 2026.

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