Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development |
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| Institution: | 1. Department of Medical Oncology, Institut Claudius Regaud, Toulouse;2. INSERM U1037, Cancer Research Center of Toulouse (CRCT), Toulouse;3. INSERM U1218, Institut Bergonié, Bordeaux;4. University of Bordeaux, Bordeaux;5. Department of Pathology, Institut Claudius Regaud, Toulouse, France;2. Instituto de Cálculo, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina;3. Dipartimento di Scienze Biochimiche, Università “Sapienza”, Rome, Italy;4. Departamento de Química Inorgánica, Analítica y Química Física and Inquimae-Conicet, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina |
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| Abstract: | DNA replication is a prerequisite for cell proliferation, yet it can be increasingly challenging for a eukaryotic cell to faithfully duplicate its genome as its size and complexity expands. Dormant origins now emerge as a key component for cells to successfully accomplish such a demanding but essential task. In this perspective, we will first provide an overview of the fundamental processes eukaryotic cells have developed to regulate origin licensing and firing. With a special focus on mammalian systems, we will then highlight the role of dormant origins in preventing replication-associated genome instability and their functional interplay with proteins involved in the DNA damage repair response for tumor suppression. Lastly, deficiencies in the origin licensing machinery will be discussed in relation to their influence on stem cell maintenance and human diseases. |
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| Keywords: | MCM2-7 Dormant replication origins Replication stress Replication-associated genome instability Stem cells Cancer Rare human genetic diseases |
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