| Title: |
Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms |
| Authors: |
Payen, Celia; Koszul, Romain; Dujon, Bernard; Fischer, Gilles |
| Contributors: |
Génétique Moléculaire des Levures; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); UPMC - UFR Sciences de la vie (UFR 927); Université Pierre et Marie Curie - Paris 6 (UPMC); This work was supported by grants from the Association pour la Recherche sur le Cancer (3266), the Agence Nationale de la Recherche (ANR-05-BLAN0331) and the CNRS (GDR2354 “Génolevures II”). BD is a member of the Institut Universitaire de France. CP is a recipient of a predoctoral fellowship of the Ministère de la Recherche through the Université Paris 6. RK was a recipient of a Bourse de Docteur Ingénieur CNRS.; We thank the “Génopole Alsace-Lorraine” and the “Génopole Institut Pasteur” for microarray hybridizations. We also thank P. Pasero for the gift of the mrc1AQ carrying strains. We are grateful to E. Fabre, G.F. Richard, B. Llorente and A Holmes for valuable comments on the manuscript and to all our colleagues from the Génolevures network and the Unité de Génétique Moléculaire des Levures for fruitful discussions.; ANR-05-BLAN-0331,GENARISE,How do genes arise ? Lessons and questions from the evolution of yeast genomes.(2005) |
| Source: |
ISSN: 1553-7390. |
| Publisher Information: |
CCSD; Public Library of Science |
| Publication Year: |
2008 |
| Subject Terms: |
MESH: Base Sequence; MESH: DNA Breaks; Double-Stranded; MESH: DNA-Binding Proteins; MESH: DNA-Directed DNA Polymerase; MESH: Endonucleases; MESH: Gene Duplication; MESH: Microsatellite Repeats; MESH: Molecular Sequence Data; MESH: Saccharomyces cerevisiae Proteins; MESH: Single-Strand Specific DNA and RNA Endonucleases; MESH: DNA Repair; MESH: DNA Repair Enzymes; MESH: DNA Replication; MESH: DNA Transposable Elements; [SDV.GEN]Life Sciences [q-bio]/Genetics |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/18773114; PUBMED: 18773114; PUBMEDCENTRAL: PMC2518615 |
| DOI: |
10.1371/journal.pgen.1000175 |
| Availability: |
https://pasteur.hal.science/pasteur-03376840; https://pasteur.hal.science/pasteur-03376840v1/document; https://pasteur.hal.science/pasteur-03376840v1/file/pgen.1000175.pdf; https://doi.org/10.1371/journal.pgen.1000175 |
| Rights: |
http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.44E9F93D |
| Database: |
BASE |