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Segmental Duplications Arise From Pol32-Dependent Repair Of Broken Forks Through Two Alternative Replication-Based Mechanisms
Celia Payen, R. Koszul, B. Dujon, G. Fischer
Published 2008 · Medicine, Biology
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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 Polδ 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.
This paper references
Amplification of histone genes by circular chromosome formation in Saccharomyces cerevisiae
Diana E. Libuda (2006)
Mechanisms of Rad52-Independent Spontaneous and UV-Induced Mitotic Recombination in Saccharomyces cerevisiae
Eric Coïc (2008)
Quantifying the mechanisms for segmental duplications in mammalian genomes by statistical analysis and modeling.
Y. Zhou (2005)
An Alu transposition model for the origin and expansion of human segmental duplications.
J. Bailey (2003)
Break-induced replication: What is it and what is it for?
B. Llorente (2008)
Birth of Two Chimeric Genes in the Hominidae Lineage
A. Courseaux (2001)
Segmental duplications in euchromatic regions of human chromosome 5: a source of evolutionary instability and transcriptional innovation.
A. Courseaux (2003)
Rad52-independent mitotic gene conversion in Saccharomyces cerevisiae frequently results in chromosomal loss.
J. Haber (1985)
Division of labor at the eukaryotic replication fork.
S. A. Nick McElhinny (2008)
Live-Cell Imaging Reveals Replication of Individual Replicons in Eukaryotic Replication Factories
E. Kitamura (2006)
Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae
K. Myung (2001)
Segmental duplications and evolutionary plasticity at tumor chromosome break-prone regions.
Eva Darai-Ramqvist (2008)
Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome
A. Sharp (2006)
Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification
G. Schleiermacher (2007)
Reactivation of the ATCase domain of the URA2 gene complex: a positive selection method for Ty insertions and chromosomal rearrangements in Saccharomyces cerevisiae
F. Roelants (2004)
Stability of Large Segmental Duplications in the Yeast Genome
R. Koszul (2006)
DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues.
Y. Hsiang (1989)
Global variation in copy number in the human genome
R. Redon (2006)
Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants
C. Chen (1999)
The Rad1-Rad10 Complex Promotes the Production of Gross Chromosomal Rearrangements From Spontaneous DNA Damage in Saccharomyces cerevisiae
Ji-Young Hwang (2005)
Break-induced replication and telomerase-independent telomere maintenance require Pol32
John R. Lydeard (2007)
Replication-Based Mechanisms of DNA Duplications PLoS Genetics | www.plosgenetics
CLB5 and CLB6, a new pair of B cyclins involved in DNA replication in Saccharomyces cerevisiae.
E. Schwob (1993)
Characterization of RAD51-Independent Break-Induced Replication That Acts Preferentially with Short Homologous Sequences
G. Ira (2002)
Characterizing the cancer genome in lung adenocarcinoma
B. Weir (2007)
E Kitamura (2006)
Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication
P. Pisitkun (2006)
Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair.
M. Bauters (2008)
Removal of nonhomologous DNA ends in double-strand break recombination: the role of the yeast ultraviolet repair gene RAD1.
J. Fishman-Lobell (1992)
Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation
R. Ullmann (2007)
CLB5-dependent activation of late replication origins in S. cerevisiae.
A. Donaldson (1998)
Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication.
A. Malkova (1996)
Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution
Zhaoshi Jiang (2007)
Diminished S-Phase Cyclin-Dependent Kinase Function Elicits Vital Rad53-Dependent Checkpoint Responses in Saccharomyces cerevisiae
D. Gibson (2004)
Mutational and selective effects on copy-number variants in the human genome
G. Cooper (2007)
Dual roles for DNA sequence identity and the mismatch repair system in the regulation of mitotic crossing-over in yeast.
A. Datta (1997)
Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome
J. Korbel (2007)
Replication dynamics of the yeast
MK Raghuraman (2001)
Induction of genome instability by DNA damage in Saccharomyces cerevisiae.
K. Myung (2003)
RAD51-Dependent Break-Induced Replication in Yeast
A. Davis (2004)
Template switching during break-induced replication
C. E. Smith (2007)
A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders
J. Lee (2007)
The distribution of the numbers of mutants in bacterial populations
D. Lea (2008)
APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy
A. Rovelet-Lecrux (2006)
Maintenance of fork integrity at damaged DNA and natural pause sites.
H. Tourrière (2007)
Aneuploidy acts both oncogenically and as a tumor suppressor.
Beth A. A. Weaver (2007)
Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis.
E. Winzeler (1999)
Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors
J. Pollack (2002)
A 2.3 Mb duplication of chromosome 8q24.3 associated with severe mental retardation and epilepsy detected by standard karyotype
M. Bonaglia (2005)
Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast.
A. Admire (2006)
The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes.
Kouji Inoue (2001)
Double complex mutations involving F8 and FUNDC2 caused by distinct break‐induced replication
C. Sheen (2007)
Mechanisms of Rad52Independent Spontaneous and UV-Induced Mitotic Recombination in Saccharomyces cerevisiae
E Coic (2008)
Replication dynamics of the yeast genome.
M. Raghuraman (2001)
Primate segmental duplications: crucibles of evolution, diversity and disease
J. Bailey (2006)
Comparative genomics of hemiascomycete yeasts: genes involved in DNA replication, repair, and recombination.
G. Richard (2005)
The estimation of mutation rates from incompletely tested gametes, and the detection of mutations in mammals
D. Falconer (2008)
Yeast Mre11 and Rad1 Proteins Define a Ku-Independent Mechanism To Repair Double-Strand Breaks Lacking Overlapping End Sequences
J. Ma (2003)
Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans
T. Aitman (2006)
Eucaryotic genome evolution through the spontaneous duplication of large chromosomal segments
R. Koszul (2004)
Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53.
Alexander J. Osborn (2003)
Duplication processes in Saccharomyces cerevisiae haploid strains
Joseph Schacherer (2005)
A 2.|E|-Bit Distributed Algorithm for the Directed Euler Trail Problem
Wen-Huei Chen (1993)
RAD51-Dependent Break-Induced Replication Differs in Kinetics and Checkpoint Responses from RAD51-Mediated Gene Conversion
A. Malkova (2005)
Preferential Occurrence of Chromosome Breakpoints within Early Replicating Regions in Neuroblastoma
I. Janoueix-Lerosey (2005)
The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility
E. González (2005)
Replication in Hydroxyurea: It's a Matter of Time
G. Alvino (2007)
Identification of Saccharomyces cerevisiae DNA ligase IV: involvement in DNA double‐strand break repair
S. Teo (1997)
Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia
I. Lahortiga (2007)
DNA Replication Fork Pause Sites Dependent on Transcription
A. Deshpande (1996)
Mechanism of DNA double-strand break repair by non-homologous end joining.
Melissa L Hefferin (2005)
Yeast DNA ligase IV mediates non-homologous DNA end joining
T. Wilson (1997)
CLB5: a novel B cyclin from budding yeast with a role in S phase.
C. Epstein (1992)
This paper is referenced by
Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants.
M. Arlt (2009)
Mus81 and Yen1 promote reciprocal exchange during mitotic recombination to maintain genome integrity in budding yeast.
C. K. Ho (2010)
Fusion of nearby inverted repeats by a replication-based mechanism leads to formation of dicentric and acentric chromosomes that cause genome instability in budding yeast.
Andrew L Paek (2009)
An evolutionary driver of interspersed segmental duplications in primates
Stuart Cantsilieris (2020)
Break-induced replication: functions and molecular mechanism.
A. Malkova (2013)
SINE Retrotransposon variation drives Ecotypic disparity in natural populations of Coilia nasus
Dong Hua Liu (2020)
Palindromic gene amplification — an evolutionarily conserved role for DNA inverted repeats in the genome
H. Tanaka (2009)
Human and chimpanzee Luteinizing hormone/ Chorionic Gonadotropin beta (LHB/CGB) gene clusters: diversity and divergence of young duplicated genes
P. Hallast (2009)
Title: Transposition-mediated DNA re-replication in maize
Jianbo Zhang (2014)
DISSERTATION INVESTIGATION OF MECHANISMS OF MITOTIC RECOMBINATION IN YEAST Submitted by Lisa Victoria Harcy Graduate Degree Program in Cell and Molecular Biology In partial fulfillment of the requirements For the Degree of Doctor of Philosophy
Lucas Argueso (2016)
What have studies of genomic disorders taught us about our genome?
Alexandra D. Simmons (2012)
The replication fork's five degrees of freedom, their failure and genome rearrangements.
T. Weinert (2009)
Two routes to senescence revealed by real-time analysis of telomerase-negative single lineages
Zhou Xu (2015)
The causes of replication stress and their consequences on genome stability and cell fate.
Indiana Magdalou (2014)
The origins and impact of primate segmental duplications.
Tomàs Marquès-Bonet (2009)
Comparative genomics of protoploid Saccharomycetaceae.
J. Souciet (2009)
Origin-Dependent Inverted-Repeat Amplification: A Replication-Based Model for Generating Palindromic Amplicons
B. Brewer (2011)
Genetic Characterization and Analysis of Cis and Trans-elements That Facilitate Genome Stability in Saccharomyces cerevisiae
Hope Jones (2010)
Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae
H. Zhang (2013)
A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation
P. Hastings (2009)
Repeat expansion in the budding yeast ribosomal DNA can occur independently of the canonical homologous recombination machinery
Jonathan Houseley (2011)
Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders
J. Iyer (2014)
The Repertoire and Dynamics of Evolutionary Adaptations to Controlled Nutrient-Limited Environments in Yeast
D. Gresham (2008)
Environmental change drives accelerated adaptation through stimulated copy number variation
R. M. Hull (2017)
Homologous Recombination and the Formation of Complex Genomic Rearrangements.
A. Piazza (2019)
Alterations in DNA Replication and Histone Levels Promote Histone Gene Amplification in Saccharomyces cerevisiae
Diana E. Libuda (2010)
Global Chromosomal Structural Instability in a Subpopulation of Starving Escherichia coli Cells
D. Lin (2011)
The biogenesis of chromosome translocations
Vassilis Roukos (2014)
Leaping forks at inverted repeats.
D. Branzei (2010)
Mechanism of tandem duplication formation in BRCA1 mutant cells
Nicholas A Willis (2017)
Loss of DNA Replication Control Is a Potent Inducer of Gene Amplification
B. Green (2010)
Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements.
Cynthia J. Sakofsky (2015)See more