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Regulatory Mechanisms That Prevent Re-initiation of DNA Replication Can Be Locally Modulated at Origins by Nearby Sequence Elements


Eukaryotic organisms have hundreds to thousands of DNA replication origins distributed throughout their genomes. Faithful duplication of these genomes requires a multitude of global controls that ensure that every replication origin initiates at most once per cell cycle. Disruptions in these controls can result in re-initiation of origins and localized re-replication of the surrounding genome. Such re-replicated genomic segments are converted to stable chromosomal alterations with extraordinarily efficiency and could provide a potential source of genomic alterations associated with cancer cells. This publication establishes the existence of a local layer of replication control by identifying new genetic elements, termed re-initiation promoters (RIPs) that can locally override some of the global mechanisms preventing re-initiation. Origins adjacent to RIP elements are not as tightly controlled and thus more susceptible to re-initiation, especially when these global controls are compromised. We speculate that RIP elements contribute to genomic variability in origin control and make some regions of the genome more susceptible to re-replication induced genomic instability.


Vyšlo v časopise: Regulatory Mechanisms That Prevent Re-initiation of DNA Replication Can Be Locally Modulated at Origins by Nearby Sequence Elements. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004358
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004358

Souhrn

Eukaryotic organisms have hundreds to thousands of DNA replication origins distributed throughout their genomes. Faithful duplication of these genomes requires a multitude of global controls that ensure that every replication origin initiates at most once per cell cycle. Disruptions in these controls can result in re-initiation of origins and localized re-replication of the surrounding genome. Such re-replicated genomic segments are converted to stable chromosomal alterations with extraordinarily efficiency and could provide a potential source of genomic alterations associated with cancer cells. This publication establishes the existence of a local layer of replication control by identifying new genetic elements, termed re-initiation promoters (RIPs) that can locally override some of the global mechanisms preventing re-initiation. Origins adjacent to RIP elements are not as tightly controlled and thus more susceptible to re-initiation, especially when these global controls are compromised. We speculate that RIP elements contribute to genomic variability in origin control and make some regions of the genome more susceptible to re-replication induced genomic instability.


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