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Cited by 200DNA Repair MechanismsGenomic variations and chromosomal abnormalitiesGenome Rearrangement Algorithms

Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms

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Payen, Celia, Koszul, Romain, Dujon, Bernard, Fischer, Gilles·2008·PLoS Genetics
DOI 10.1371/journal.pgen.1000175PMC PMC2518615
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Abstract

The propensity of segmental duplications (SDs) to promote genomic instability is of increasing interest since their involvement in numerous human genomic diseases and cancers was revealed. However, the mechanism(s) responsible for their appearance remain mostly speculative. Here, we show that in budding yeast, replication accidents, which are most likely transformed into broken forks, play a causal role in the formation of SDs. The Pol32 subunit of the major replicative polymerase Poldelta is required for all SD formation, demonstrating that SDs result from untimely DNA synthesis rather than from unequal crossing-over. Although Pol32 is known to be required for classical (Rad52-dependant) break-induced replication, only half of the SDs can be attributed to this mechanism. The remaining SDs are generated through a Rad52-independent mechanism of template switching between microsatellites or microhomologous sequences. This new mechanism, named microhomology/microsatellite-induced replication (MMIR), differs from all known DNA double-strand break repair pathways, as MMIR-mediated duplications still occur in the combined absence of homologous recombination, microhomology-mediated, and nonhomologous end joining machineries. The interplay between these two replication-based pathways explains important features of higher eukaryotic genomes, such as the strong, but not strict, association between SDs and transposable elements, as well as the frequent formation of oncogenic fusion genes generating protein innovations at SD junctions.

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Cited by

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Authors
Payen, C., Koszul, R., Dujon, B., & Fischer, G.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Fischer, Gilles
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2008-09-05
Volume
4
Issue
9
Pages
e1000175
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1000175
PMC
PMC2518615
OpenAlex
W2038462200
Cited by
200
References
0
Citations by year
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FWCI
8.65
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Association pour la Recherche sur le Cancer
  • Agence Nationale de la Recherche (ANR-05-BLAN-0331, ANR-05)
  • Centre National de la Recherche Scientifique
  • Institut Universitaire de France
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
Keywords
segmental duplication, Pol32, break-induced replication, microhomology-mediated recombination, template switching, DNA double-strand break repair, genomic instability, transposable elements, fusion oncogenes, Saccharomyces cerevisiae
MeSH terms
Base Sequence, DNA Transposable Elements, DNA-Directed DNA Polymerase, DNA Repair, DNA Replication, DNA-Binding Proteins, Endonucleases, Molecular Sequence Data, Single-Strand Specific DNA and RNA Endonucleases, Microsatellite Repeats, Gene Duplication, Saccharomyces cerevisiae Proteins, DNA Repair Enzymes, DNA Breaks, Double-Stranded

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