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  1. Article ; Online: Mechanism for inverted-repeat recombination induced by a replication fork barrier.

    Marie, Léa / Symington, Lorraine S

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 32

    Abstract: Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. To gain insight into the mechanism of recombination between repeated sequences in the context of replication stress, we ... ...

    Abstract Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. To gain insight into the mechanism of recombination between repeated sequences in the context of replication stress, we used a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome. Our study reveals that the replication fork block stimulates a unique recombination pathway dependent on Rad51 strand invasion and Rad52-Rad59 strand annealing activities, Mph1/Rad5 fork remodelers, Mre11/Exo1/Dna2 resection machineries, Rad1-Rad10 nuclease and DNA polymerase δ. Furthermore, we show recombination at stalled replication forks is limited by the Srs2 helicase and Mus81-Mms4/Yen1 nucleases. Physical analysis of the replication-associated recombinants revealed that half are associated with an inversion of sequence between the repeats. Based on our extensive genetic characterization, we propose a model for recombination of closely linked repeats that can robustly generate chromosome rearrangements.
    MeSH term(s) Chromosomes ; DEAD-box RNA Helicases/metabolism ; DNA Helicases/metabolism ; DNA Replication ; DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; Exodeoxyribonucleases ; Flap Endonucleases ; Genomic Instability ; Neoplasms/genetics ; Rad52 DNA Repair and Recombination Protein/metabolism ; Recombination, Genetic ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances DNA-Binding Proteins ; RAD52 protein, S cerevisiae ; RAD52 protein, human ; RAD59 protein, S cerevisiae ; Rad52 DNA Repair and Recombination Protein ; Saccharomyces cerevisiae Proteins ; SRS2 protein, S cerevisiae (125481-05-2) ; Endonucleases (EC 3.1.-) ; Exodeoxyribonucleases (EC 3.1.-) ; Flap Endonucleases (EC 3.1.-) ; MUS81 protein, S cerevisiae (EC 3.1.-) ; exodeoxyribonuclease I (EC 3.1.11.1) ; MMS4 protein, S cerevisiae (EC 3.1.22.-) ; MPH1 protein, S cerevisiae (EC 3.6.1.-) ; RAD5 protein, S cerevisiae (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; DNA2 protein, S cerevisiae (EC 3.6.4.12) ; DEAD-box RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2022-01-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-27443-w
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  2. Article: Double-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ and Rad51-dependent mechanism.

    Al-Zain, Amr / Nester, Mattie R / Symington, Lorraine S

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Inverted duplications, also known as foldback inversions, are commonly observed in cancers and are the major class of chromosome rearrangement recovered from yeast cells lacking Mre11 nuclease. Foldback priming at naturally occurring inverted repeats is ... ...

    Abstract Inverted duplications, also known as foldback inversions, are commonly observed in cancers and are the major class of chromosome rearrangement recovered from yeast cells lacking Mre11 nuclease. Foldback priming at naturally occurring inverted repeats is one mechanism proposed for the generation of inverted duplications. However, the initiating lesion for these events and the mechanism by which they form has not been fully elucidated. Here, we show that a DNA double-strand break (DSB) induced near natural short, inverted repeats drives high frequency inverted duplication in Sae2 and Mre11-deficient cells. We find that DNA polymerase δ proof-reading activity acts non-redundantly with Rad1 nuclease to remove heterologous tails formed during foldback annealing. Additionally, Pol32 is required for the generation of inverted duplications, suggesting that Pol δ catalyzes fill-in synthesis primed from the foldback to create a hairpin-capped chromosome that is subsequently replicated to form a dicentric isochromosome. Stabilization of the dicentric chromosome after breakage involves telomere capture by non-reciprocal translocation mediated by repeat sequences and requires Rad51.
    Language English
    Publishing date 2023-01-25
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.24.525421
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  3. Article ; Online: Mechanism for inverted-repeat recombination induced by a replication fork barrier

    Léa Marie / Lorraine S. Symington

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 13

    Abstract: Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. Here the authors use a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted ... ...

    Abstract Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. Here the authors use a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome to support a model for recombination of closely linked repeats at stalled replication forks.
    Keywords Science ; Q
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: DNA end resection during homologous recombination.

    Gnügge, Robert / Symington, Lorraine S

    Current opinion in genetics & development

    2021  Volume 71, Page(s) 99–105

    Abstract: Exposure to environmental mutagens but also cell-endogenous processes can create DNA double-strand breaks (DSBs) in a cell's genome. DSBs need to be repaired accurately and timely to ensure genomic integrity and cell survival. One major DSB repair ... ...

    Abstract Exposure to environmental mutagens but also cell-endogenous processes can create DNA double-strand breaks (DSBs) in a cell's genome. DSBs need to be repaired accurately and timely to ensure genomic integrity and cell survival. One major DSB repair mechanism, called homologous recombination, relies on the nucleolytic degradation of the 5'-terminated strands in a process termed end resection. Here, we review new insights into end resection with a focus on the mechanistic interplay of the nucleases, helicases, and accessory factors involved.
    MeSH term(s) DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA Helicases/genetics ; DNA Repair/genetics ; Homologous Recombination/genetics
    Chemical Substances DNA (9007-49-2) ; DNA Helicases (EC 3.6.4.-)
    Language English
    Publishing date 2021-07-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1077312-5
    ISSN 1879-0380 ; 0959-437X
    ISSN (online) 1879-0380
    ISSN 0959-437X
    DOI 10.1016/j.gde.2021.07.004
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    Zs.A 3240: Show issues Location:
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  5. Article ; Online: DNA End Resection: Mechanism and Control.

    Cejka, Petr / Symington, Lorraine S

    Annual review of genetics

    2021  Volume 55, Page(s) 285–307

    Abstract: DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genome integrity and cell viability. Typically, cells repair DSBs by either nonhomologous end joining (NHEJ) or homologous recombination (HR). The relative use of these two pathways ... ...

    Abstract DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genome integrity and cell viability. Typically, cells repair DSBs by either nonhomologous end joining (NHEJ) or homologous recombination (HR). The relative use of these two pathways depends on many factors, including cell cycle stage and the nature of the DNA ends. A critical determinant of repair pathway selection is the initiation of 5'→3' nucleolytic degradation of DNA ends, a process referred to as DNA end resection. End resection is essential to create single-stranded DNA overhangs, which serve as the substrate for the Rad51 recombinase to initiate HR and are refractory to NHEJ repair. Here, we review recent insights into the mechanisms of end resection, how it is regulated, and the pathological consequences of its dysregulation.
    MeSH term(s) DNA ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/genetics ; DNA Repair/genetics ; DNA-Binding Proteins/metabolism ; Exodeoxyribonucleases/genetics ; Exodeoxyribonucleases/metabolism ; Homologous Recombination/genetics
    Chemical Substances DNA-Binding Proteins ; DNA (9007-49-2) ; Exodeoxyribonucleases (EC 3.1.-)
    Language English
    Publishing date 2021-11-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 207928-8
    ISSN 1545-2948 ; 0066-4170 ; 0066-4197
    ISSN (online) 1545-2948
    ISSN 0066-4170 ; 0066-4197
    DOI 10.1146/annurev-genet-071719-020312
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  6. Article ; Online: Long-range DNA end resection supports homologous recombination by checkpoint activation rather than extensive homology generation.

    Kimble, Michael T / Johnson, Matthew J / Nester, Mattie R / Symington, Lorraine S

    eLife

    2023  Volume 12

    Abstract: Homologous recombination (HR), the high-fidelity mechanism for double-strand break (DSB) repair, relies on DNA end resection by nucleolytic degradation of the 5'-terminated ends. However, the role of long-range resection mediated by Exo1 and/or Sgs1-Dna2 ...

    Abstract Homologous recombination (HR), the high-fidelity mechanism for double-strand break (DSB) repair, relies on DNA end resection by nucleolytic degradation of the 5'-terminated ends. However, the role of long-range resection mediated by Exo1 and/or Sgs1-Dna2 in HR is not fully understood. Here, we show that Exo1 and Sgs1 are dispensable for recombination between closely linked repeats, but are required for interchromosomal repeat recombination in
    MeSH term(s) Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Homologous Recombination ; Exodeoxyribonucleases/genetics ; Exodeoxyribonucleases/metabolism ; DNA/metabolism ; RecQ Helicases/metabolism
    Chemical Substances Saccharomyces cerevisiae Proteins ; Exodeoxyribonucleases (EC 3.1.-) ; DNA (9007-49-2) ; RecQ Helicases (EC 3.6.4.12)
    Language English
    Publishing date 2023-06-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.84322
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  7. Article: Genetic reporters to detect and quantify homologous recombination in yeast.

    Marie, Léa / Kimble, Michael T / Symington, Lorraine S

    Methods in cell biology

    2022  Volume 182, Page(s) 35–48

    Abstract: Homologous recombination is a conserved process that cells use to repair damaged DNA. Many genetic assays have been developed in Saccharomyces cerevisiae to measure and characterize different types of recombination events, as well as identify proteins ... ...

    Abstract Homologous recombination is a conserved process that cells use to repair damaged DNA. Many genetic assays have been developed in Saccharomyces cerevisiae to measure and characterize different types of recombination events, as well as identify proteins acting in such recombination events. Here, we describe two intrachromosomal reporters that utilize ade2 heteroalleles, whereby homologous recombination can be detected by colony color and adenine prototrophy. We detail the use of these reporters to measure recombination frequency, as well as to characterize the types of recombination events.
    MeSH term(s) Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Homologous Recombination/genetics ; DNA Damage ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; DNA Repair
    Chemical Substances Saccharomyces cerevisiae Proteins
    Language English
    Publishing date 2022-11-28
    Publishing country United States
    Document type Journal Article
    ISSN 0091-679X
    ISSN 0091-679X
    DOI 10.1016/bs.mcb.2022.10.011
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  8. Article ; Online: Sequence and chromatin features guide DNA double-strand break resection initiation.

    Gnügge, Robert / Reginato, Giordano / Cejka, Petr / Symington, Lorraine S

    Molecular cell

    2023  Volume 83, Issue 8, Page(s) 1237–1250.e15

    Abstract: DNA double-strand breaks (DSBs) are cytotoxic genome lesions that must be accurately and efficiently repaired to ensure genome integrity. In yeast, the Mre11-Rad50-Xrs2 (MRX) complex nicks 5'-terminated DSB ends to initiate nucleolytic processing of DSBs ...

    Abstract DNA double-strand breaks (DSBs) are cytotoxic genome lesions that must be accurately and efficiently repaired to ensure genome integrity. In yeast, the Mre11-Rad50-Xrs2 (MRX) complex nicks 5'-terminated DSB ends to initiate nucleolytic processing of DSBs for repair by homologous recombination. How MRX-DNA interactions support 5' strand-specific nicking and how nicking is influenced by the chromatin context have remained elusive. Using a deep sequencing-based assay, we mapped MRX nicks at single-nucleotide resolution next to multiple DSBs in the yeast genome. We observed that the DNA end-binding Ku70-Ku80 complex directed DSB-proximal nicks and that repetitive MRX cleavage extended the length of resection tracts. We identified a sequence motif and a DNA meltability profile that is preferentially nicked by MRX. Furthermore, we found that nucleosomes as well as transcription impeded MRX incisions. Our findings suggest that local DNA sequence and chromatin features shape the activity of this central DSB repair complex.
    MeSH term(s) DNA Breaks, Double-Stranded ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Chromatin/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Endodeoxyribonucleases/genetics ; Exodeoxyribonucleases/genetics ; DNA Repair ; DNA/genetics
    Chemical Substances Chromatin ; Saccharomyces cerevisiae Proteins ; Endodeoxyribonucleases (EC 3.1.-) ; Exodeoxyribonucleases (EC 3.1.-) ; DNA (9007-49-2)
    Language English
    Publishing date 2023-03-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2023.02.010
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    Zs.A 5055: Show issues Location:
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  9. Article ; Online: Efficient DNA double-strand break formation at single or multiple defined sites in the Saccharomyces cerevisiae genome.

    Gnügge, Robert / Symington, Lorraine S

    Nucleic acids research

    2020  Volume 48, Issue 20, Page(s) e115

    Abstract: DNA double-strand breaks (DSBs) are common genome lesions that threaten genome stability and cell survival. Cells use sophisticated repair machineries to detect and heal DSBs. To study DSB repair pathways and associated factors, inducible site-specific ... ...

    Abstract DNA double-strand breaks (DSBs) are common genome lesions that threaten genome stability and cell survival. Cells use sophisticated repair machineries to detect and heal DSBs. To study DSB repair pathways and associated factors, inducible site-specific endonucleases have proven to be fundamental tools. In Saccharomyces cerevisiae, galactose-inducible rare-cutting endonucleases are commonly used to create a single DSB at a unique cleavage site. Galactose induction requires cell cultivation in suboptimal growth media, which is tedious especially when working with slow growing DSB repair mutants. Moreover, endonucleases that simultaneously create DSBs in multiple defined and unique loci of the yeast genome are not available, hindering studies of DSB repair in different genomic regions and chromatin contexts. Here, we present new tools to overcome these limitations. We employ a heterologous media-independent induction system to express the yeast HO endonuclease or bacterial restriction enzymes for single or multiple DSB formation, respectively. The systems facilitate tightly controlled and efficient DSB formation at defined genomic sites and will be valuable tools to study DSB repair at a local and genome-wide scale.
    MeSH term(s) Bacteria/enzymology ; DNA Breaks, Double-Stranded ; DNA Restriction Enzymes/genetics ; DNA Restriction Enzymes/metabolism ; Gene Expression/genetics ; Genetic Engineering ; Genome, Fungal ; Promoter Regions, Genetic ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances Saccharomyces cerevisiae Proteins ; DNA Restriction Enzymes (EC 3.1.21.-)
    Language English
    Publishing date 2020-11-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkaa833
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    Zs.A 1067: Show issues Location:
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  10. Article ; Online: Recognition for Discoveries in DNA Repair.

    Klein, Hannah L / Symington, Lorraine S

    The New England journal of medicine

    2019  Volume 381, Issue 7, Page(s) 677–679

    MeSH term(s) Animals ; Awards and Prizes ; Biological Science Disciplines/history ; Chromosome Breakage ; DNA Repair/genetics ; Gene Editing ; History of Medicine ; History, 21st Century ; Mammals ; Recombination, Genetic ; United States
    Language English
    Publishing date 2019-08-14
    Publishing country United States
    Document type Historical Article ; Journal Article
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMcibr1907358
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