Stage-Specific Regulation of DNA Damage Repair by the Circadian Regulator, CRY1, in Prostate Cancer.

Jun 4, 2026bioRxiv : the preprint server for biology

How the Body Clock Protein CRY1 Controls DNA Repair at Different Stages in Prostate Cancer

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Abstract

Circadian cryptochrome 1 (CRY1) is identified as a key factor influencing DNA damage response pathways in prostate cancer.

CRY1 promotes non-homologous end joining (NHEJ) and base excision repair (BER) in hormone-sensitive prostate cancer.
In castration-resistant prostate cancer, CRY1 drives a switch towards dependence on homologous recombination (HR).
CRY1 links cell growth signals to genome maintenance, allowing tumor cells to manage DNA damage and continue progressing.
Loss of CRY1 reveals specific vulnerabilities in DNA repair pathways, indicating potential targets for treatment.
These findings suggest that targeting CRY1 could enhance the effectiveness of DNA damage response inhibitors.

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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.

Stage-Specific Regulation of DNA Damage Repair by the Circadian Regulator, CRY1, in Prostate Cancer.

Abstract

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