Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication
Summary: Genome stability requires coordination of DNA replication origin activation and replication fork progression. RTEL1 is a regulator of homologous recombination (HR) implicated in meiotic cross-over control and DNA repair in C. elegans. Through a genome-wide synthetic lethal screen, we uncove...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720306288 |
| _version_ | 1818776974622982144 |
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| author | Roberto Bellelli Jillian Youds Valerie Borel Jennifer Svendsen Visnja Pavicic-Kaltenbrunner Simon J. Boulton |
| author_facet | Roberto Bellelli Jillian Youds Valerie Borel Jennifer Svendsen Visnja Pavicic-Kaltenbrunner Simon J. Boulton |
| author_sort | Roberto Bellelli |
| collection | DOAJ |
| description | Summary: Genome stability requires coordination of DNA replication origin activation and replication fork progression. RTEL1 is a regulator of homologous recombination (HR) implicated in meiotic cross-over control and DNA repair in C. elegans. Through a genome-wide synthetic lethal screen, we uncovered an essential genetic interaction between RTEL1 and DNA polymerase (Pol) epsilon. Loss of POLE4, an accessory subunit of Pol epsilon, has no overt phenotype in worms. In contrast, the combined loss of POLE-4 and RTEL-1 results in embryonic lethality, accumulation of HR intermediates, genome instability, and cessation of DNA replication. Similarly, loss of Rtel1 in Pole4−/− mouse cells inhibits cellular proliferation, which is associated with persistent HR intermediates and incomplete DNA replication. We propose that RTEL1 facilitates genome-wide fork progression through its ability to metabolize DNA secondary structures that form during DNA replication. Loss of this function becomes incompatible with cell survival under conditions of reduced origin activation, such as Pol epsilon hypomorphy. |
| first_indexed | 2024-12-18T11:21:27Z |
| format | Article |
| id | doaj.art-4d69e63d68a149aa9cf2b97e4f59eeef |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-18T11:21:27Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-4d69e63d68a149aa9cf2b97e4f59eeef2022-12-21T21:09:49ZengElsevierCell Reports2211-12472020-05-01318Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA ReplicationRoberto Bellelli0Jillian Youds1Valerie Borel2Jennifer Svendsen3Visnja Pavicic-Kaltenbrunner4Simon J. Boulton5The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UKThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UKThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UKThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UKThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UKThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Corresponding authorSummary: Genome stability requires coordination of DNA replication origin activation and replication fork progression. RTEL1 is a regulator of homologous recombination (HR) implicated in meiotic cross-over control and DNA repair in C. elegans. Through a genome-wide synthetic lethal screen, we uncovered an essential genetic interaction between RTEL1 and DNA polymerase (Pol) epsilon. Loss of POLE4, an accessory subunit of Pol epsilon, has no overt phenotype in worms. In contrast, the combined loss of POLE-4 and RTEL-1 results in embryonic lethality, accumulation of HR intermediates, genome instability, and cessation of DNA replication. Similarly, loss of Rtel1 in Pole4−/− mouse cells inhibits cellular proliferation, which is associated with persistent HR intermediates and incomplete DNA replication. We propose that RTEL1 facilitates genome-wide fork progression through its ability to metabolize DNA secondary structures that form during DNA replication. Loss of this function becomes incompatible with cell survival under conditions of reduced origin activation, such as Pol epsilon hypomorphy.http://www.sciencedirect.com/science/article/pii/S2211124720306288RTEL1DNA polymerase epsilonDNA replicationorigin activationgenome stability |
| spellingShingle | Roberto Bellelli Jillian Youds Valerie Borel Jennifer Svendsen Visnja Pavicic-Kaltenbrunner Simon J. Boulton Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication Cell Reports RTEL1 DNA polymerase epsilon DNA replication origin activation genome stability |
| title | Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication |
| title_full | Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication |
| title_fullStr | Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication |
| title_full_unstemmed | Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication |
| title_short | Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication |
| title_sort | synthetic lethality between dna polymerase epsilon and rtel1 in metazoan dna replication |
| topic | RTEL1 DNA polymerase epsilon DNA replication origin activation genome stability |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720306288 |
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