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Deciphering Replication Readiness and Its Role in Genome Duplication Surveillance

Cel

Errors in DNA replication are a major driver of human disease—up to two-thirds of all cancers originate from faults in this process. While we understand how cells replicate their DNA once the process begins, we know far less about how they prepare for this critical event. How do cells determine they are ready to copy their genome, and what happens when this readiness fails?

Building on recent discoveries from my lab, I propose that before entering S phase, cells undergo a tightly regulated state of replication readiness—an inheritable condition that preconfigures accurate genome duplication across generations. My data suggest this readiness precedes the G1 phase and relies on the mother cell passing the key molecular components of replication readiness to daughter cells. This creates a form of cellular memory that ensures replication fidelity across generations. The REWIRE project will define how replication readiness is established, monitored, and re-established under stress. I hypothesize the existence of a previously unrecognized G2/M surveillance mechanism—a maternal replication readiness checkpoint—safeguarding the handover of replication competence to progeny. I will also investigate how this process is established de novo during tissue regeneration—a costly and error-prone transition that may compromise genome stability.

To this end, I will use advanced tools developed in my lab, including inducible protein degradation, CRISPR-based editing, and AI-assisted single-cell and single-molecule imaging pipelines. Using small intestinal organoids, I will cross-examine inherited and de novo replication readiness and link it to tissue-level outcomes in regeneration and disease. By uncovering how cells preconfigure genome duplication before it begins, REWIRE will redefine the logic of DNA replication control, reveal new mechanisms safeguarding genome stability, and uncover vulnerabilities that could be targeted in cancer and other replication-driven disorders.

Dziedzina nauki (EuroSciVoc)

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System finansowania

HORIZON-ERC - HORIZON ERC Grants

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Zaproszenie do składania wniosków

(odnośnik otworzy się w nowym oknie) ERC-2026-STG

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Instytucja przyjmująca

BIOFYZIKALNI USTAV AKADEMIE VED CESKE REPUBLIKY
Wkład UE netto
€ 1 999 875,00
Koszt całkowity
€ 1 999 875,00

Beneficjenci (1)