scholarly journals Faculty Opinions recommendation of TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells.

2022 ◽  
Author(s):  
Ian D Hickson ◽  
Ying Liu
Keyword(s):  
Break Induced Replication

scholarly journals Rad51-Independent Interchromosomal Double-Strand Break Repair by Gene Conversion Requires Rad52 but Not Rad55, Rad57, or Dmc1

2007 ◽  
Vol 28 (3) ◽  
pp. 897-906 ◽  
Author(s):  
Thomas J. Pohl ◽  
Jac A. Nickoloff
Keyword(s):  
Gene Conversion ◽  
Strand Break ◽  
Double Strand Break ◽  
Single Strand ◽  
Homology Search ◽  
Wild Type ◽  
Dsb Repair ◽  
Single Strand Annealing ◽  
In The Wild ◽  
Break Induced Replication

ABSTRACT Homologous recombination (HR) is critical for DNA double-strand break (DSB) repair and genome stabilization. In yeast, HR is catalyzed by the Rad51 strand transferase and its “mediators,” including the Rad52 single-strand DNA-annealing protein, two Rad51 paralogs (Rad55 and Rad57), and Rad54. A Rad51 homolog, Dmc1, is important for meiotic HR. In wild-type cells, most DSB repair results in gene conversion, a conservative HR outcome. Because Rad51 plays a central role in the homology search and strand invasion steps, DSBs either are not repaired or are repaired by nonconservative single-strand annealing or break-induced replication mechanisms in rad51Δ mutants. Although DSB repair by gene conversion in the absence of Rad51 has been reported for ectopic HR events (e.g., inverted repeats or between plasmids), Rad51 has been thought to be essential for DSB repair by conservative interchromosomal (allelic) gene conversion. Here, we demonstrate that DSBs stimulate gene conversion between homologous chromosomes (allelic conversion) by >30-fold in a rad51Δ mutant. We show that Rad51-independent allelic conversion and break-induced replication occur independently of Rad55, Rad57, and Dmc1 but require Rad52. Unlike DSB-induced events, spontaneous allelic conversion was detected in both rad51Δ and rad52Δ mutants, but not in a rad51Δ rad52Δ double mutant. The frequencies of crossovers associated with DSB-induced gene conversion were similar in the wild type and the rad51Δ mutant, but discontinuous conversion tracts were fivefold more frequent and tract lengths were more widely distributed in the rad51Δ mutant, indicating that heteroduplex DNA has an altered structure, or is processed differently, in the absence of Rad51.

Yeastspt6-140Mutation, Affecting Chromatin and Transcription, Preferentially Increases Recombination in Which Rad51p-Mediated Strand Exchange Is Dispensable

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 597-611 ◽  
Author(s):  
Francisco Malagón ◽  
Andrés Aguilera
Keyword(s):  
Strand Exchange ◽  
Micrococcal Nuclease ◽  
Sensitivity Analyses ◽  
Inverted Repeats ◽  
Major Mechanism ◽  
Spontaneous Recombination ◽  
Single Strand Annealing ◽  
Strand Invasion ◽  
Strand Annealing ◽  
Break Induced Replication

AbstractWe have shown that the spt6-140 and spt4-3 mutations, affecting chromatin structure and transcription, stimulate recombination between inverted repeats by a RAD52-dependent mechanism that is very efficient in the absence of RAD51, RAD54, RAD55, and RAD57. Such a mechanism of recombination is RAD1-RAD59-dependent and yields gene conversions highly associated with the inversion of the repeat. The spt6-140 mutation alters transcription and chromatin in our inverted repeats, as determined by Northern and micrococcal nuclease sensitivity analyses, respectively. Hyper-recombination levels are diminished in the absence of transcription. We believe that the chromatin alteration, together with transcription impairment caused by spt6-140, increases the incidence of spontaneous recombination regardless of whether or not it is mediated by Rad51p-dependent strand exchange. Our results suggest that spt6, as well as spt4, primarily stimulates a mechanism of break-induced replication. We discuss the possibility that the chromatin alteration caused by spt6-140 facilitates a Rad52p-mediated one-ended strand invasion event, possibly inefficient in wild-type chromatin. Our results are consistent with the idea that the major mechanism leading to inversions might not be crossing over but break-induced replication followed by single-strand annealing.

scholarly journals Multiple Heterologies Increase Mitotic Double-Strand Break-Induced Allelic Gene Conversion Tract Lengths in Yeast

Genetics ◽  
1999 ◽  
Vol 153 (2) ◽  
pp. 665-679 ◽  
Author(s):  
Jac A Nickoloff ◽  
Douglas B Sweetser ◽  
Jennifer A Clikeman ◽  
Guru Jot Khalsa ◽  
Sarah L Wheeler
Keyword(s):  
Gene Conversion ◽  
Mismatch Repair ◽  
Frameshift Mutation ◽  
Strand Break ◽  
Double Strand Break ◽  
Chromosome Loss ◽  
Allelic Gene ◽  
Break Induced Replication ◽  
Gene Conversion Tract ◽  
Conversion Tract

Abstract Spontaneous and double-strand break (DSB)-induced allelic recombination in yeast was investigated in crosses between ura3 heteroalleles inactivated by an HO site and a +1 frameshift mutation, with flanking markers defining a 3.4-kbp interval. In some crosses, nine additional phenotypically silent RFLP mutations were present at ∼100-bp intervals. Increasing heterology from 0.2 to 1% in this interval reduced spontaneous, but not DSB-induced, recombination. For DSB-induced events, 75% were continuous tract gene conversions without a crossover in this interval; discontinuous tracts and conversions associated with a crossover each comprised ∼7% of events, and 10% also converted markers in unbroken alleles. Loss of heterozygosity was seen for all markers centromere distal to the HO site in 50% of products; such loss could reflect gene conversion, break-induced replication, chromosome loss, or G2 crossovers. Using telomere-marked strains we determined that nearly all allelic DSB repair occurs by gene conversion. We further show that most allelic conversion results from mismatch repair of heteroduplex DNA. Interestingly, markers shared between the sparsely and densely marked interval converted at higher rates in the densely marked interval. Thus, the extra markers increased gene conversion tract lengths, which may reflect mismatch repair-induced recombination, or a shift from restoration- to conversion-type repair.

scholarly journals Repairing a double–strand chromosome break by homologous recombination: revisiting Robin Holliday's model

2004 ◽  
Vol 359 (1441) ◽  
pp. 79-86 ◽  
Author(s):  
James E. Haber ◽  
Gregorz Ira ◽  
Anna Malkova ◽  
Neal Sugawara
Keyword(s):  
Homologous Recombination ◽  
Repair Process ◽  
Strand Break ◽  
Holliday Junctions ◽  
Chromosome Break ◽  
Invasion Mechanism ◽  
Strand Invasion ◽  
Strand Annealing ◽  
Break Induced Replication ◽  
Mutant Cells

Since the pioneering model for homologous recombination proposed by Robin Holliday in 1964, there has been great progress in understanding how recombination occurs at a molecular level. In the budding yeast Saccharomyces cerevisiae , one can follow recombination by physically monitoring DNA after the synchronous induction of a double–strand break (DSB) in both wild–type and mutant cells. A particularly well–studied system has been the switching of yeast mating–type ( MAT ) genes, where a DSB can be induced synchronously by expression of the site–specific HO endonuclease. Similar studies can be performed in meiotic cells, where DSBs are created by the Spo11 nuclease. There appear to be at least two competing mechanisms of homologous recombination: a synthesis–dependent strand annealing pathway leading to noncrossovers and a two–end strand invasion mechanism leading to formation and resolution of Holliday junctions (HJs), leading to crossovers. The establishment of a modified replication fork during DSB repair links gene conversion to another important repair process, break–induced replication. Despite recent revelations, almost 40 years after Holliday's model was published, the essential ideas he proposed of strand invasion and heteroduplex DNA formation, the formation and resolution of HJs, and mismatch repair, remain the basis of our thinking.

scholarly journals Checkpoint Adaptation Precedes Spontaneous and Damage-Induced Genomic Instability in Yeast

2001 ◽  
Vol 21 (5) ◽  
pp. 1710-1718 ◽  
Author(s):  
David J. Galgoczy ◽  
David P. Toczyski
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genomic Instability ◽  
Cell Cycle Progression ◽  
Repair Process ◽  
Yeast Cells ◽  
Chromosome Loss ◽  
Checkpoint Adaptation ◽  
Block Cell Cycle Progression ◽  
Break Induced Replication

ABSTRACT Despite the fact that eukaryotic cells enlist checkpoints to block cell cycle progression when their DNA is damaged, cells still undergo frequent genetic rearrangements, both spontaneously and in response to genotoxic agents. We and others have previously characterized a phenomenon (adaptation) in which yeast cells that are arrested at a DNA damage checkpoint eventually override this arrest and reenter the cell cycle, despite the fact that they have not repaired the DNA damage that elicited the arrest. Here, we use mutants that are defective in checkpoint adaptation to show that adaptation is important for achieving the highest possible viability after exposure to DNA-damaging agents, but it also acts as an entrée into some forms of genomic instability. Specifically, the spontaneous and X-ray-induced frequencies of chromosome loss, translocations, and a repair process called break-induced replication occur at significantly reduced rates in adaptation-defective mutants. This indicates that these events occur after a cell has first arrested at the checkpoint and then adapted to that arrest. Because malignant progression frequently involves loss of genes that function in DNA repair, adaptation may promote tumorigenesis by allowing genomic instability to occur in the absence of repair.

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