Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance.
Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-06-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3116906?pdf=render |
| _version_ | 1811219579757658112 |
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| author | Seiji Tanaka Hiroyuki Araki |
| author_facet | Seiji Tanaka Hiroyuki Araki |
| author_sort | Seiji Tanaka |
| collection | DOAJ |
| description | Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase is genotoxic and induces genomic instability in the budding yeast Saccharomyces cerevisiae. Our data indicate that cells preserve a low level of the initiation factor Sld2 to prevent untimely initiation during the normal cell cycle in addition to controlling the phosphorylation of Sld2 and Sld3 by cyclin-dependent kinase. Although untimely activation of origin is inhibited on multiple levels, we show that deregulation of a single pathway can cause genomic instability, such as gross chromosome rearrangements (GCRs). Furthermore, simultaneous deregulation of multiple pathways causes an even more severe phenotype. These findings highlight the importance of having multiple inhibitory mechanisms to prevent the untimely initiation of chromosome replication to preserve stable genome maintenance over generations in eukaryotes. |
| first_indexed | 2024-04-12T07:29:08Z |
| format | Article |
| id | doaj.art-6db8e3d397d64d719a97f9041dd54533 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T07:29:08Z |
| publishDate | 2011-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-6db8e3d397d64d719a97f9041dd545332022-12-22T03:42:07ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-06-0176e100213610.1371/journal.pgen.1002136Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance.Seiji TanakaHiroyuki ArakiGenomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase is genotoxic and induces genomic instability in the budding yeast Saccharomyces cerevisiae. Our data indicate that cells preserve a low level of the initiation factor Sld2 to prevent untimely initiation during the normal cell cycle in addition to controlling the phosphorylation of Sld2 and Sld3 by cyclin-dependent kinase. Although untimely activation of origin is inhibited on multiple levels, we show that deregulation of a single pathway can cause genomic instability, such as gross chromosome rearrangements (GCRs). Furthermore, simultaneous deregulation of multiple pathways causes an even more severe phenotype. These findings highlight the importance of having multiple inhibitory mechanisms to prevent the untimely initiation of chromosome replication to preserve stable genome maintenance over generations in eukaryotes.http://europepmc.org/articles/PMC3116906?pdf=render |
| spellingShingle | Seiji Tanaka Hiroyuki Araki Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. PLoS Genetics |
| title | Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. |
| title_full | Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. |
| title_fullStr | Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. |
| title_full_unstemmed | Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. |
| title_short | Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. |
| title_sort | multiple regulatory mechanisms to inhibit untimely initiation of dna replication are important for stable genome maintenance |
| url | http://europepmc.org/articles/PMC3116906?pdf=render |
| work_keys_str_mv | AT seijitanaka multipleregulatorymechanismstoinhibituntimelyinitiationofdnareplicationareimportantforstablegenomemaintenance AT hiroyukiaraki multipleregulatorymechanismstoinhibituntimelyinitiationofdnareplicationareimportantforstablegenomemaintenance |