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Chong Wang, James Higgins, Yi He, Pingli Lu, Dabing Zhang, Wanqi Liang
Yen1/GEN1 are canonical Holliday Junction (HJ) resolvases that belong to the RAD2/XPG family. In eukaryotes, such as budding yeast, mice, worms, and humans, Yen1/GEN1 work together with Mus81-Mms4/MUS81-EME1 and Slx1-Slx4/SLX1-SLX4 in DNA repair by homologous recombination to maintain genome stability. In plants, the biological function of Yen1/GEN1 remains largely unclear. In this study, we characterized the loss of function mutants of OsGEN1 and OsSEND1, a pair of paralogs of Yen1/GEN1 in rice. We first investigated the role of OsGEN1 during meiosis and found a reduction in chiasma frequency by ~6% in osgen1 mutants, compared to wild type, suggesting a possible involvement of OsGEN1 in the formation of crossovers...
January 3, 2017: Plant Physiology
Jane C Kim, Samantha T Harris, Teresa Dinter, Kartik A Shah, Sergei M Mirkin
Expansions of (CAG)n/(CTG)n trinucleotide repeats are responsible for over a dozen neuromuscular and neurodegenerative disorders. Large-scale expansions are commonly observed in human pedigrees and may be explained by iterative small-scale events such as strand slippage during replication or repair DNA synthesis. Alternatively, a distinct mechanism may lead to a large-scale repeat expansion as a single step. To distinguish between these possibilities, we developed a novel experimental system specifically tuned to analyze large-scale expansions of (CAG)n/(CTG)n repeats in Saccharomyces cerevisiae...
January 2017: Nature Structural & Molecular Biology
Gizem Ölmezer, Maryna Levikova, Dominique Klein, Benoît Falquet, Gabriele Alessandro Fontana, Petr Cejka, Ulrich Rass
Cells have evolved mechanisms to protect, restart and repair perturbed replication forks, allowing full genome duplication, even under replication stress. Interrogating the interplay between nuclease-helicase Dna2 and Holliday junction (HJ) resolvase Yen1, we find the Dna2 helicase activity acts parallel to homologous recombination (HR) in promoting DNA replication and chromosome detachment at mitosis after replication fork stalling. Yen1, but not the HJ resolvases Slx1-Slx4 and Mus81-Mms4, safeguards chromosome segregation by removing replication intermediates that escape Dna2...
October 25, 2016: Nature Communications
Ibtissam Talhaoui, Manuel Bernal, Gerard Mazón
In mitotic cells, the repair of double-strand breaks by homologous recombination (HR) is important for genome integrity. HR requires the orchestration of a subset of pathways for timely removal of joint-molecule intermediates that would otherwise prevent segregation of chromosomes in mitosis. The use of nucleases to resolve recombination intermediates is important for chromosome segregation, but is hazardous because crossovers can result in loss of heterozygosity or chromosome rearrangements. Unregulated use of the nucleases involved in the resolution of recombination intermediates could also be a risk during replication...
September 2016: FEMS Yeast Research
Xiaowen Wang, Herui Wang, Bin Guo, Ya Zhang, Yinv Gong, Chi Zhang, Hong Xu, Xiaohui Wu
Resolution of the Holliday junction (HJ) is essential for homologous recombination and DNA repair. In Saccharomyces cerevisiae, HJ resolvase Yen1 and the Mus81-Mms4 complex are redundant in DNA damage repair. In cultured mammalian cells, such redundancy also exists between Yen1 ortholog GEN1 and the Mus81-Mms1 ortholog MUS81-EME1. In this report, we further tested if GEN1 and EME1 redundantly affect HJ-related physiological processes in mice. We found that combined homozygous mutations of Gen1 and Eme1 led to synthetic lethality during early embryonic stages...
October 2016: DNA and Cell Biology
Philipp Wild, Joao Matos
The establishment of stable interactions between chromosomes underpins vital cellular processes such as recombinational DNA repair and bipolar chromosome segregation. On the other hand, timely disengagement of persistent connections is necessary to assure efficient partitioning of the replicated genome prior to cell division. Whereas great progress has been made in defining how cohesin-mediated chromosomal interactions are disengaged as cells prepare to undergo chromosome segregation, little is known about the metabolism of DNA joint molecules (JMs), generated during the repair of chromosomal lesions...
June 2016: Current Opinion in Cell Biology
Miguel G Blanco, Joao Matos
Repair of DNA lesions through homologous recombination promotes the establishment of stable chromosomal interactions. Multiple helicases, topoisomerases and structure-selective endonucleases (SSEs) act upon recombining joint molecules (JMs) to disengage chromosomal connections and safeguard chromosome segregation. Recent studies on two conserved SSEs - MUS81 and Yen1/GEN1- uncovered multiple layers of regulation that operate to carefully tailor JM-processing according to specific cellular needs. Temporal restriction of SSE function imposes a hierarchy in pathway usage that ensures efficient JM-processing while minimizing reciprocal exchanges between the recombining DNAs...
2015: Frontiers in Genetics
Jonay García-Luis, Félix Machín
Downregulation of separase, condensin, Smc5/6, topoisomerase II and Cdc14 in Saccharomyces cerevisiae yields anaphase bridges formed by unresolved sister chromatids (SCBs). Here we report that the overlapping actions of the structure-selective endonucleases (SSEs) Mus81-Mms4/EME1 and Yen1/GEN1, but not Slx1-Slx4, are also essential to prevent the formation of spontaneous SCBs that depend on the homologous recombination pathway. We further show that the frequency of SCBs is boosted after mild replication stress and that they contain joint molecules enriched in non-canonical forms of the Holliday junction (HJ), including nicked-HJ (nHJ)...
2014: Nature Communications
Ying Wai Chan, Stephen C West
Holliday junction (HJ) resolvases are necessary for the processing of persistent recombination intermediates before cell division. Their actions, however, need to be restricted to the late stages of the cell cycle to avoid the inappropriate cleavage of replication intermediates. Control of the yeast HJ resolvase, Yen1, involves phosphorylation changes that modulate its catalytic activity and nuclear import. Here, we show that GEN1, the human ortholog of Yen1, is regulated by a different mechanism that is independent of phosphorylation...
September 11, 2014: Nature Communications
Karol Kramarz, Ireneusz Litwin, Magdalena Cal-Bąkowska, Barnabas Szakal, Dana Branzei, Robert Wysocki, Dorota Dziadkowiec
The Saccharomyces cerevisiae Uls1 belongs to the Swi2/Snf2 family of DNA-dependent ATPases and a new protein family of SUMO-targeted ubiquitin ligases. Here we show that Uls1 is implicated in DNA repair independently of the replication stress response pathways mediated by the endonucleases Mus81 and Yen1 and the helicases Mph1 and Srs2. Uls1 works together with Sgs1 and we demonstrate that the attenuation of replication stress-related defects in sgs1Δ by deletion of ULS1 depends on a functional of Rad51 recombinase and post-replication repair pathway mediated by Rad18 and Rad5, but not on the translesion polymerase, Rev3...
September 2014: DNA Repair
Joao Matos, Stephen C West
Holliday junctions (HJs) can be formed between sister chromatids or homologous chromosomes during the recombinational repair of DNA lesions. A variety of pathways act upon HJs to remove them from DNA, in events that are critical for appropriate chromosome segregation. Despite the identification and characterization of multiple enzymes involved in HJ processing, the cellular mechanisms that regulate and implement pathway usage have only just started to be delineated. A conserved network of core cell-cycle kinases and phosphatases modulate HJ metabolism by exerting spatial and temporal control over the activities of two structure-selective nucleases: yeast Mus81-Mms4 (human MUS81-EME1) and Yen1 (human GEN1)...
July 2014: DNA Repair
Miguel G Blanco, Joao Matos, Stephen C West
The careful orchestration of cellular events such as DNA replication, repair, and segregation is essential for equal distribution of the duplicated genome into two daughter cells. To ensure that persistent recombination intermediates are resolved prior to cell division, the Yen1 Holliday junction resolvase is activated at anaphase. Here, we show that the master cell-cycle regulators, cyclin-dependent kinase (Cdk) and Cdc14 phosphatase, control the actions of Yen1. During S phase, Cdk-mediated phosphorylation of Yen1 promotes its nuclear exclusion and inhibits catalytic activity by reducing the efficiency of DNA binding...
April 10, 2014: Molecular Cell
Christie L Eissler, Gerard Mazón, Brendan L Powers, Sergey N Savinov, Lorraine S Symington, Mark C Hall
Faithful genome transmission during cell division requires precise, coordinated action of DNA metabolic enzymes, including proteins responsible for DNA damage detection and repair. Dynamic phosphorylation plays an important role in controlling repair enzymes during the DNA damage response (DDR). Cdc14 phosphatases oppose cyclin-dependent kinase (Cdk) phosphorylation and have been implicated in the DDR in several model systems. Here, we have refined the substrate specificity of budding yeast Cdc14 and, using this insight, identified the Holliday junction resolvase Yen1 as a DNA repair target of Cdc14...
April 10, 2014: Molecular Cell
Jonay García-Luis, Andrés Clemente-Blanco, Luis Aragón, Félix Machín
The only canonical Holliday junction (HJ) resolvase identified in eukaryotes thus far is Yen1/GEN1. Nevertheless, Yen1/GEN1 appears to have a minor role in HJ resolution, and, instead, other structure-specific endonucleases (SSE) that recognize branched DNA play the leading roles, Mus81-Mms4/EME1 being the most important in budding yeast. Interestingly, cells tightly regulate the activity of each HJ resolvase during the yeast cell cycle. Thus, Mus81-Mms4 is activated in G 2/M, while Yen1 gets activated shortly afterwards...
2014: Cell Cycle
Anamarija Stafa, Roberto A Donnianni, Leonid A Timashev, Alicia F Lam, Lorraine S Symington
Chromosomal double-strand breaks (DSBs) that have only one end with homology to a donor duplex undergo repair by strand invasion followed by replication to the chromosome terminus (break-induced replication, BIR). Using a transformation-based assay system, it was previously shown that BIR could occur by several rounds of strand invasion, DNA synthesis, and dissociation. Here we describe a modification of the transformation-based assay to facilitate detection of switching between donor templates during BIR by genetic selection in diploid yeast...
April 2014: Genetics
Gerard Mazón, Lorraine S Symington
Homology-dependent repair of double-strand breaks (DSBs) from nonsister templates has the potential to generate loss of heterozygosity or genome rearrangements. Here we show that the Saccharomyces cerevisiae Mph1 helicase prevents crossovers between ectopic sequences by removing substrates for Mus81-Mms4 or Rad1-Rad10 cleavage. A role for Yen1 is only apparent in the absence of Mus81. Cells lacking Mph1 and the three nucleases are highly defective in the repair of a single DSB, suggesting that the recombination intermediates that accumulate cannot be processed by the Sgs1-Top3-Rmi1 complex (STR)...
October 10, 2013: Molecular Cell
Ulrich Rass
Genome duplication requires that replication forks track the entire length of every chromosome. When complications occur, homologous recombination-mediated repair supports replication fork movement and recovery. This leads to physical connections between the nascent sister chromatids in the form of Holliday junctions and other branched DNA intermediates. A key role in the removal of these recombination intermediates falls to structure-specific nucleases such as the Holliday junction resolvase RuvC in Escherichia coli...
December 2013: Chromosoma
Benjamin Pardo, Andrés Aguilera
DNA double-strand break (DSB) repair occurring in repeated DNA sequences often leads to the generation of chromosomal rearrangements. Homologous recombination normally ensures a faithful repair of DSBs through a mechanism that transfers the genetic information of an intact donor template to the broken molecule. When only one DSB end shares homology to the donor template, conventional gene conversion fails to occur and repair can be channeled to a recombination-dependent replication pathway termed break-induced replication (BIR), which is prone to produce chromosome non-reciprocal translocations (NRTs), a classical feature of numerous human cancers...
September 2012: PLoS Genetics
Jiang Chen, Stefan U Aström
Yen1 is a nuclease identified in Saccharomyces cerevisiae that cleaves the Holliday junction (HJ) intermediate formed during homologous recombination. Alternative routes to disjoin HJs are performed by the Mus81/Mms4- and Sgs1/Top3/Rmi1-complexes. Here, we investigate the role of the Yen1 protein in the yeast Kluyveromyces lactis. We demonstrate that both yen1 mus81 and yen1 sgs1 double mutants displayed negative genetic interactions in the presence of DNA-damaging chemicals. To test if these phenotypes required the catalytic activity of Yen1, we introduced point mutations targeting the catalytic site of Yen1, which abolished the nuclease activity in vitro...
October 1, 2012: DNA Repair
Gerard Mazón, Alicia F Lam, Chu Kwen Ho, Martin Kupiec, Lorraine S Symington
Holliday junctions can be formed during homology-dependent repair of DNA double-strand breaks, and their resolution is essential for chromosome segregation and generation of crossover products. The Mus81-Mms4 and Yen1 nucleases are required for mitotic crossovers between chromosome homologs in Saccharomyces cerevisiae; however, crossovers between dispersed repeats are still detected in their absence. Here we show that the Rad1-Rad10 nuclease promotes formation of crossover and noncrossover recombinants between ectopic sequences...
September 2012: Nature Structural & Molecular Biology
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