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Arrested replication forks guide retrotransposon integration.

ABSTRACT: Long terminal repeat (LTR) retrotransposons are an abundant class of genomic parasites that replicate by insertion of new copies into the host genome. Fungal LTR retrotransposons prevent mutagenic insertions through diverse targeting mechanisms that avoid coding sequences, but conserved principles guiding their target site selection have not been established. Here, we show that insertion of the fission yeast LTR retrotransposon Tf1 is guided by the DNA binding protein Sap1 and that the efficiency and location of the targeting depend on the activity of Sap1 as a replication fork barrier. We propose that Sap1 and the fork arrest it causes guide insertion of Tf1 by tethering the integration complex to target sites.

SUBMITTER: Jacobs JZ

PROVIDER: S-EPMC4832573 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Arrested replication forks guide retrotransposon integration.

Jacobs Jake Z JZ Rosado-Lugo Jesus D JD Cranz-Mileva Susanne S Ciccaglione Keith M KM Tournier Vincent V Zaratiegui Mikel M

Science (New York, N.Y.) 20150901 6255

Long terminal repeat (LTR) retrotransposons are an abundant class of genomic parasites that replicate by insertion of new copies into the host genome. Fungal LTR retrotransposons prevent mutagenic insertions through diverse targeting mechanisms that avoid coding sequences, but conserved principles guiding their target site selection have not been established. Here, we show that insertion of the fission yeast LTR retrotransposon Tf1 is guided by the DNA binding protein Sap1 and that the efficienc ...[more]

PMID: 26404838

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Arrested replication forks guide retrotransposon integration

Project description:Long Terminal Repeat (LTR) Retrotransposons are an abundant class of genomic parasites that replicate by insertion of new copies into the host genome. LTR retrotransposons prevent mutagenic insertions through diverse targeting mechanisms that avoid coding sequences, but a universal set of principles guiding their target site selection hasn’t been established. Here we show that insertion of the fission yeast LTR retrotransposon Tf1 is guided by the DNA binding protein Sap1, and that the efficiency and location of the targeting depend on the activity of Sap1 as a replication fork barrier. We propose that Sap1 guides insertion of Tf1 by blocking the progression of the replication fork, and that the Tf1 transposon uses features of arrested forks to insert into the host genome. These observations point to a universal mechanism for determination of LTR retrotransposon target site selection.

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Histone deposition promotes recombination-dependent replication at arrested forks.

Project description:Replication stress poses a serious threat to genome stability. Recombination-Dependent-Replication (RDR) promotes DNA synthesis resumption from arrested forks. Despite the identification of chromatin restoration pathways after DNA repair, crosstalk coupling RDR and chromatin assembly is largely unexplored. The fission yeast Chromatin Assembly Factor-1, CAF-1, is known to promote RDR. Here, we addressed the contribution of histone deposition to RDR. We expressed a mutated histone, H3-H113D, to genetically alter replication-dependent chromatin assembly by destabilizing (H3-H4)2 tetramer. We established that DNA synthesis-dependent histone deposition, by CAF-1 and Asf1, promotes RDR by preventing Rqh1-mediated disassembly of joint-molecules. The recombination factor Rad52 promotes CAF-1 binding to sites of recombination-dependent DNA synthesis, indicating that histone deposition occurs downstream Rad52. Histone deposition and Rqh1 activity act synergistically to promote cell resistance to camptothecin, a topoisomerase I inhibitor that induces replication stress. Moreover, histone deposition favors non conservative recombination events occurring spontaneously in the absence of Rqh1, indicating that the stabilization of joint-molecules by histone deposition also occurs independently of Rqh1 activity. These results indicate that histone deposition plays an active role in promoting RDR, a benefit counterbalanced by stabilizing at-risk joint-molecules for genome stability.

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Project description:Homologous recombination is a universal mechanism that allows repair of DNA and provides support for DNA replication. Homologous recombination is therefore a major pathway that suppresses non-homology-mediated genome instability. Here, we report that recovery of impeded replication forks by homologous recombination is error-prone. Using a fork-arrest-based assay in fission yeast, we demonstrate that a single collapsed fork can cause mutations and large-scale genomic changes, including deletions and translocations. Fork-arrest-induced gross chromosomal rearrangements are mediated by inappropriate ectopic recombination events at the site of collapsed forks. Inverted repeats near the site of fork collapse stimulate large-scale genomic changes up to 1,500 times over spontaneous events. We also show that the high accuracy of DNA replication during S-phase is impaired by impediments to fork progression, since fork-arrest-induced mutation is due to erroneous DNA synthesis during recovery of replication forks. The mutations caused are small insertions/duplications between short tandem repeats (micro-homology) indicative of replication slippage. Our data establish that collapsed forks, but not stalled forks, recovered by homologous recombination are prone to replication slippage. The inaccuracy of DNA synthesis does not rely on PCNA ubiquitination or trans-lesion-synthesis DNA polymerases, and it is not counteracted by mismatch repair. We propose that deletions/insertions, mediated by micro-homology, leading to copy number variations during replication stress may arise by progression of error-prone replication forks restarted by homologous recombination.

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CENP-B preserves genome integrity at replication forks paused by retrotransposon LTR.

Project description:Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centromeric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and promotes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentromeric heterochromatin and tandem satellite repeats.

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SUMO protease and proteasome recruitment at the nuclear periphery differently affect replication dynamics at arrested forks.

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The end-joining factor Ku acts in the end-resection of double strand break-free arrested replication forks.

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Nascent DNA processing by RecJ favors lesion repair over translesion synthesis at arrested replication forks in Escherichia coli.

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