Mus81-Mms4 and Yen1 resolve a novel anaphase bridge formed by noncanonical Holliday junctions

García-Luis, Jonay; Machín, Félix

doi:10.1038/ncomms6652

Cited by 51 publications

(68 citation statements)

References 68 publications

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“…We propose that these simpler structures may be more important in vivo , perhaps because they are more frequently encountered. Consistent with this hypothesis, recent studies show that replicative stress in yeast results in nicked and gapped HJs, while another study highlights non-HJ intermediates of replication repair (56,57). …”

Section: Discussionmentioning

confidence: 64%

Substrate preference of Gen endonucleases highlights the importance of branched structures as DNA damage repair intermediates

Bellendir

Morris

et al. 2017

Nucleic Acids Research

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Human GEN1 and yeast Yen1 are endonucleases with the ability to cleave Holliday junctions (HJs), which are proposed intermediates in recombination. In vivo, GEN1 and Yen1 function secondarily to Mus81, which has weak activity on intact HJs. We show that the genetic relationship is reversed in Drosophila, with Gen mutants having more severe defects than mus81 mutants. In vitro, DmGen, like HsGEN1, efficiently cleaves HJs, 5΄ flaps, splayed arms, and replication fork structures. We find that the cleavage rates for 5΄ flaps are significantly higher than those for HJs for both DmGen and HsGEN1, even in vast excess of enzyme over substrate. Kinetic studies suggest that the difference in cleavage rates results from a slow, rate-limiting conformational change prior to HJ cleavage: formation of a productive dimer on the HJ. Despite the stark difference in vivo that Drosophila uses Gen over Mus81 and humans use MUS81 over GEN1, we find the in vitro activities of DmGen and HsGEN1 to be strikingly similar. These findings suggest that simpler branched structures may be more important substrates for Gen orthologs in vivo, and highlight the utility of using the Drosophila model system to further understand these enzymes.

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Section: Discussionmentioning

confidence: 64%

Substrate preference of Gen endonucleases highlights the importance of branched structures as DNA damage repair intermediates

Bellendir

Morris

et al. 2017

Nucleic Acids Research

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“…Our observation that LOH is much more common in chromosomes that have become trisomic argues for a direct linkage between mitotic recombination and defective chromosome segregation. In this regard, it has been recently shown that persistent recombination intermediates form anaphase bridges (García-Luis and Machín 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Samples were treated and analyzed using a BD FACScalibur machine as previously described (Quevedo et al 2012;García-Luis and Machín 2014). Briefly, 300 ml of culture was taken and mixed with 900 ml of 100% ethanol.…”

Section: Fluorescence-activated Cell Sorting Analysismentioning

confidence: 99%

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae

et al. 2015

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Genomic instability is a common feature found in cancer cells . Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanisms that explain cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient loss yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes, and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity, are detected mainly on the ribosomal DNAbearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins, and controlling spindle dynamics in a well-defined window within anaphase, we speculate that the transient loss of Cdc14 activity causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny. KEYWORDS Cdc14; Saccharomyces cerevisiae; gross chromosomal rearrangements; aneuploidy; caretaker genes G ENOMIC instability is one of the hallmarks of cancer cells. Many genomic alterations result in gene dose variation including deletions/duplication, gross chromosomal rearrangements (GCRs), and aneuploidy; loss of heterozygosity (LOH) associated with mitotic recombination is also observed (Hanahan and Weinberg 2011). In wild-type cells, specialized mechanisms exist, such as cell cycle checkpoints and DNA repair activities, which suppress genome instability. Genes encoding for proteins that protect cells from cancer-related genomic instability are referred to as caretakers. Many of the tumor suppressor genes identified in familiar cancer-prone syndromes are caretakers. Although caretakers are not directly responsible for the decision of a cell to divide, their loss leads cells to rapidly accumulate genomic aberrations and mutations that potentially result in disorganization of cell division and their subsequent transformation into cancer cells (Kinzler and Vogelstein 1997;van Heemst et al. 2007). For example, mutations in genes involved in DNA repair pathways such as nonhomologous end joining, homologous recombination, mismatch repair, base excision repair, and nucleotide excision repair have been shown to lead to the accumulation of mutations within the genome that significantly increase the risk of carcinogenesis (Negrini et al. 2010; Aguilera and García-Muse 2013 protein (BLM) ac...

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“…HR often leads to the formation of DNA joint molecules in which the two recombining DNAs are covalently connected by a four-way DNA junction or Holliday junction (HJ) [25–27]. These intermediates can result in chromosome segregation defects if they are not processed before anaphase onset [28–32]. …”

Section: The Origin Of Hr-ufbsmentioning

confidence: 99%

“…Persistent recombination intermediates that escape the attentions of BTR, or are refractory to dissolution (e.g. single HJs and D-loop structures), are processed by a second mechanism which involves structure-selective endonuclease (SSE)-mediated resolution [31,32,39,40]. There are two genetically distinct resolution pathways: one is mediated by the SLX1–SLX4, MUS81-EME1 and XPF-ERCC1 (SMX) tri-nuclease complex [27,31,41–46], and the other is mediated by GEN1 endonuclease [47–50].…”

Section: The Origin Of Hr-ufbsmentioning

confidence: 99%

A new class of ultrafine anaphase bridges generated by homologous recombination

Chan

West

2018

Cell Cycle

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Ultrafine anaphase bridges (UFBs) are a potential source of genome instability that is a hallmark of cancer. UFBs can arise from DNA catenanes at centromeres/rDNA loci, late replication intermediates induced by replication stress, and DNA linkages at telomeres. Recently, it was reported that DNA intertwinements generated by homologous recombination give rise to a new class of UFBs, which have been termed homologous recombination ultrafine bridges (HR-UFBs). HR-UFBs are decorated with PICH and BLM in anaphase, and are subsequently converted to RPA-coated, single-stranded DNA bridges. Breakage of these sister chromatid entanglements leads to DNA damage that can be repaired by non-homologous end joining in the next cell cycle, but the potential consequences include DNA rearrangements, chromosome translocations and fusions. Visualisation of these HR-UFBs, and knowledge of how they arise, provides a molecular basis to explain how upregulation of homologous recombination or failure to resolve recombination intermediates leads to the development of chromosomal instability observed in certain cancers.

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Mus81-Mms4 and Yen1 resolve a novel anaphase bridge formed by noncanonical Holliday junctions

Cited by 51 publications

References 68 publications

Substrate preference of Gen endonucleases highlights the importance of branched structures as DNA damage repair intermediates

Substrate preference of Gen endonucleases highlights the importance of branched structures as DNA damage repair intermediates

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae

A new class of ultrafine anaphase bridges generated by homologous recombination

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