Slx5-Slx8 ubiquitin ligase targets active pools of the Yen1 nuclease to limit crossover formation

Talhaoui, Ibtissam; Bernal, Manuel; Mullen, Janet R.; Dorison, Hugo; Palancade, Benoı̂t; Brill, Steven J.; Mazón, Gerard

doi:10.1038/s41467-018-07364-x

Cited by 21 publications

(47 citation statements)

References 65 publications

(92 reference statements)

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“…While dna2 Δ pif1-m2 cells contained a similar number of Yen1-EGFP foci associated with Nop1-RFP, co-localization decreased to 58 ± 2% due to an increase in Yen1 foci not marked by Nop1 (Figure 4F , G ). These finding are consistent with the notion that Yen1 target structures are predominantly associated with the rDNA ( 53 ) and elevated elsewhere in the genome in dna2 Δ pif1-m2 cells after RS, in line with our PFGE analyses showing a genome-wide replication defect in the absence of Dna2.…”

Section: Resultssupporting

confidence: 92%

“…In some cases, Yen1-EGFP assembled into foci on circular structures that emanated from the bridge between the separating nuclei (Figure 4C ). These structures were suggestive of rDNA-loops ( 51 , 52 ), consistent with previous findings in unperturbed conditions that Yen1 mainly accumulates within the rDNA ( 53 ). To address the co-localization of RS-induced Yen1 foci with the rDNA, we expressed nucleolar protein Nop1 ( 54 ) tagged with RFP in pif1-m2 cells and dna2 Δ pif1-m2 cells.…”

Section: Resultssupporting

confidence: 91%

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Disease-associated DNA2 nuclease–helicase protects cells from lethal chromosome under-replication

Falquet

Ölmezer

Enkner

et al. 2020

Nucleic Acids Research

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DNA2 is an essential nuclease–helicase implicated in DNA repair, lagging-strand DNA synthesis, and the recovery of stalled DNA replication forks (RFs). In Saccharomyces cerevisiae, dna2Δ inviability is reversed by deletion of the conserved helicase PIF1 and/or DNA damage checkpoint-mediator RAD9. It has been suggested that Pif1 drives the formation of long 5′-flaps during Okazaki fragment maturation, and that the essential function of Dna2 is to remove these intermediates. In the absence of Dna2, 5′-flaps are thought to accumulate on the lagging strand, resulting in DNA damage-checkpoint arrest and cell death. In line with Dna2’s role in RF recovery, we find that the loss of Dna2 results in severe chromosome under-replication downstream of endogenous and exogenous RF-stalling. Importantly, unfaithful chromosome replication in Dna2-mutant cells is exacerbated by Pif1, which triggers the DNA damage checkpoint along a pathway involving Pif1’s ability to promote homologous recombination-coupled replication. We propose that Dna2 fulfils its essential function by promoting RF recovery, facilitating replication completion while suppressing excessive RF restart by recombination-dependent replication (RDR) and checkpoint activation. The critical nature of Dna2’s role in controlling the fate of stalled RFs provides a framework to rationalize the involvement of DNA2 in Seckel syndrome and cancer.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 91%

Disease-associated DNA2 nuclease–helicase protects cells from lethal chromosome under-replication

Falquet

Ölmezer

Enkner

et al. 2020

Nucleic Acids Research

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“…Genetic data support a positive influence of Uls1 on Yen1 function, which may explain why uls1Δ sensitizes rad54/rdh54 mutants (Shah et al 2010;Bauer et al 2019). The story gets more complicated as Yen1 was also found to be ubiquitinated by Slx5/8 (Talhaoui et al 2018). Given that both Slx5/8 and Uls1 can remove sumoylated proteins, it will be interesting to test whether they regulate Yen1 in this manner and how such a potential effect may influence HJ removal.…”

Section: Sumoylation Collaborates With Phosphorylation To Regulate Hjmentioning

confidence: 99%

Intricate SUMO-based control of the homologous recombination machinery

Dhingra

Zhao

2019

Genes Dev.

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The homologous recombination (HR) machinery plays multiple roles in genome maintenance. Best studied in the context of DNA double-stranded break (DSB) repair, recombination enzymes can cleave, pair, and unwind DNA molecules, and collaborate with regulatory proteins to execute multiple DNA processing steps before generating specific repair products. HR proteins also help to cope with problems arising from DNA replication, modulating impaired replication forks or filling DNA gaps. Given these important roles, it is not surprising that each HR step is subject to complex regulation to adjust repair efficiency and outcomes as well as to limit toxic intermediates. Recent studies have revealed intricate regulation of all steps of HR by the protein modifier SUMO, which has been increasingly recognized for its broad influence in nuclear functions. This review aims to connect established roles of SUMO with its newly identified effects on recombinational repair and stimulate further thought on many unanswered questions.Homologous recombination is critical for several aspects of life, ranging from DNA repair and genome duplication to gamete production. Our understanding of HR pathways has benefited from a combination of assay systems. In cells, the generation of a defined DSB allows quantitative assessment of the status of the broken DNA molecules and the repair proteins at a temporal resolution, as well as determination of the genetic requirement for each step of repair (Haber 2016). Extensive biochemical analyses and more recently single molecule experiments have further defined the activities of HR enzymes and elucidated how they can collaborate in multiple HR steps. Several recent reviews have discussed these findings in detail (Symington et al. 2014;Heyer 2015;Ranjha et al. 2018); thus, we give only a brief overview here for each HR step to provide the context of SUMO-based regulation. As the HR machinery and its sumoylation are best examined in budding yeast, we use this system as an index for summarizing SUMO-based control. We also discuss additional regulation in mammalian cells and highlight their similarities and differences with those found in yeast. It is noteworthy that SUMO plays important roles in modulating protein recruitment to damaged chromatin and in other DNA break repair pathways. As these topics have been well covered in other reviews (Schwertman et al. 2016; Garvin and Morris 2017), they are not addressed here in order to maintain the focus on the regulation of core HR machinery.

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“…It has been demonstrated that in response to DNA damage Yen1 becomes SUMOylated and ubiquitinated by Siz1/Siz2 SUMO ligases and the Slx5-Slx8 ubiquitin ligase complex, respectively. Lack of Slx5-Slx8 maintains Yen1 in a constant SUMOylated state, a situation that stabilizes the protein and relocates it to nuclear foci [138]. In agreement with this SUMO-dependent hyper-activated state of the nuclease, a mutation in the ubiquitin acceptor site (K714) produces an increase in CO formation in response to DNA damage.…”

Section: Yen1: the Last Chance To Resolve Dna Linkagesmentioning

confidence: 82%

Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation

San-Segundo

Clemente‐Blanco

2020

Genes

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The execution of recombinational pathways during the repair of certain DNA lesions or in the meiotic program is associated to the formation of joint molecules that physically hold chromosomes together. These structures must be disengaged prior to the onset of chromosome segregation. Failure in the resolution of these linkages can lead to chromosome breakage and nondisjunction events that can alter the normal distribution of the genomic material to the progeny. To avoid this situation, cells have developed an arsenal of molecular complexes involving helicases, resolvases, and dissolvases that recognize and eliminate chromosome links. The correct orchestration of these enzymes promotes the timely removal of chromosomal connections ensuring the efficient segregation of the genome during cell division. In this review, we focus on the role of different DNA processing enzymes that collaborate in removing the linkages generated during the activation of the homologous recombination machinery as a consequence of the appearance of DNA breaks during the mitotic and meiotic programs. We will also discuss about the temporal regulation of these factors along the cell cycle, the consequences of their loss of function, and their specific role in the removal of chromosomal links to ensure the accurate segregation of the genomic material during cell division.

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Slx5-Slx8 ubiquitin ligase targets active pools of the Yen1 nuclease to limit crossover formation

Cited by 21 publications

References 65 publications

Disease-associated DNA2 nuclease–helicase protects cells from lethal chromosome under-replication

Disease-associated DNA2 nuclease–helicase protects cells from lethal chromosome under-replication

Intricate SUMO-based control of the homologous recombination machinery

Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation

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