Circadian dysregulation is increasingly linked to prostate cancer (PCa) progression, yet its role in directing DNA damage response (DDR) pathway selection remains poorly understood. Here, we identify circadian cryptochrome 1 (CRY1), a core circadian regulator, as a stage-specific determinant of DDR dependencies. Integrated transcriptomic and CRISPR-based analyses reveal that CRY1 promotes non-homologous end joining (NHEJ) and base excision repair (BER)-associated programs in hormone-sensitive disease (HTS), while driving a switch toward homologous recombination (HR) dependency in castration-resistant prostate cancer (CRPC). Mechanistically, CRY1 couples proliferative signaling to genome maintenance, enabling tumor cells to tolerate genotoxic stress and sustain progression. Notably, loss of CRY1 exposes distinct, context-dependent DDR vulnerabilities, revealing repair plasticity as a targetable actionable feature of disease evolution. These findings position CRY1 as a central regulator of DDR rewiring and support CRY1-directed combination strategies with DDR inhibitors as a rationale to delay or prevent progression to advanced, treatment-resistant PCa.
bioRxiv : the preprint server for biology. 2026 May 21*** epublish ***
Arwa Fallatah, Stefan DiFazio, Lakshmi Ravindranath, Thomas Janas, Filippo Pederzoli, Laila Scroggins, Noor Eldeen Abdalla, Orly Richter, Sally Elsamanoudi, Amina Ali, Jiji Jiang, Isabell Sesterhenn, Cara Schafer, Massimo Loda, Gregory Chesnut, Xiaofeng A Su, Christopher M McNair, Karen E Knudsen, Ayesha A Shafi