Online citations, reference lists, and bibliographies.
← Back to Search

Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading To Complex Chromosomal Rearrangements.

Cynthia J. Sakofsky, Sandeep Ayyar, A. Deem, Woo-hyun Chung, G. Ira, A. Malkova
Published 2015 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
Complex genomic rearrangements (CGRs) are a hallmark of many human diseases. Recently, CGRs were suggested to result from microhomology-mediated break-induced replication (MMBIR), a replicative mechanism involving template switching at positions of microhomology. Currently, the cause of MMBIR and the proteins mediating this process remain unknown. Here, we demonstrate in yeast that a collapse of homology-driven break-induced replication (BIR) caused by defective repair DNA synthesis in the absence of Pif1 helicase leads to template switches involving 0-6 nt of homology, followed by resolution of recombination intermediates into chromosomal rearrangements. Importantly, we show that these microhomology-mediated template switches, indicative of MMBIR, are driven by translesion synthesis (TLS) polymerases Polζ and Rev1. Thus, an interruption of BIR involving fully homologous chromosomes in yeast triggers a switch to MMBIR catalyzed by TLS polymerases. Overall, our study provides important mechanistic insights into the initiation of MMBIR associated with genomic rearrangements, similar to those promoting diseases in humans.
This paper references
10.1038/ng.944
Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome
C. Carvalho (2011)
10.1038/emboj.2010.267
Pif1- and Exo1-dependent nucleases coordinate checkpoint activation following telomere uncapping
James M. Dewar (2010)
10.1016/j.cell.2007.11.037
A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders
J. Lee (2007)
10.1534/genetics.108.087940
Defective Break-Induced Replication Leads to Half-Crossovers in Saccharomyces cerevisiae
A. Deem (2008)
10.1038/nrg2593
Mechanisms of change in gene copy number
P. Hastings (2009)
10.1016/j.cell.2010.11.055
Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development
P. Stephens (2011)
10.1038/ng.564
Mutation spectrum revealed by breakpoint sequencing of human germline CNVs
D. Conrad (2010)
10.18632/ONCOTARGET.2501
Human PIF1 helicase supports DNA replication and cell growth under oncogenic-stress
Mary E. Gagou (2014)
10.1093/hmg/ddp306
Rare pathogenic microdeletions and tandem duplications are microhomology-mediated and stimulated by local genomic architecture.
L. Vissers (2009)
10.1016/j.cell.2010.10.027
A Human Genome Structural Variation Sequencing Resource Reveals Insights into Mutational Mechanisms
J. Kidd (2010)
10.1126/SCIENCE.7545955
TLC1: template RNA component of Saccharomyces cerevisiae telomerase.
M. S. Singer (1994)
10.1038/nature12584
Migrating bubble during break-induced replication drives conservative DNA synthesis
N. Saini (2013)
10.1038/nature05723
Template switching during break-induced replication
C. E. Smith (2007)
10.1371/journal.pgen.1000327
A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation
P. Hastings (2009)
10.1038/ng.2760
Pan-cancer patterns of somatic copy-number alteration
T. Zack (2013)
10.1371/journal.pgen.1005050
Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication
C. Beck (2015)
10.1038/nature10910
Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes
J. Molenaar (2012)
10.1038/nature14493
CHROMOTHRIPSIS FROM DNA DAMAGE IN MICRONUCLEI
C. Zhang (2015)
10.1126/science.1243211
Break-Induced Replication Repair of Damaged Forks Induces Genomic Duplications in Human Cells
L. Costantino (2014)
10.2307/3760517
Guide to yeast genetics and molecular biology
C. Guthrie (1993)
10.1073/pnas.1004326107
Microhomology-mediated and nonhomologous repair of a double-strand break in the chloroplast genome of Arabidopsis
Taegun Kwon (2010)
10.1109/TCBB.2014.2359450
MMBIRFinder: A Tool to Detect Microhomology-Mediated Break-Induced Replication
M. Segar (2015)
10.1016/0092-8674(94)90179-1
The saccharomyces PIF1 DNA helicase inhibits telomere elongation and de novo telomere formation
V. Schulz (1994)
10.1007/s00439-012-1216-9
Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage–fusion–bridge for telomere stabilization
S. Yatsenko (2012)
10.1016/j.ajhg.2015.01.021
Absence of heterozygosity due to template switching during replicative rearrangements.
C. Carvalho (2015)
formation: beyond breakage-fusion-bridge for telomere
T. I. Zack (2013)
10.1371/journal.pbio.1000594
Break-Induced Replication Is Highly Inaccurate
A. Deem (2011)
10.1016/j.celrep.2014.04.053
Break-induced replication is a source of mutation clusters underlying kataegis.
Cynthia J. Sakofsky (2014)
10.1371/journal.pgen.1000175
Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms
Celia Payen (2008)
10.1371/journal.pgen.1002981
De Novo CNV Formation in Mouse Embryonic Stem Cells Occurs in the Absence of Xrcc4-Dependent Nonhomologous End Joining
M. Arlt (2012)
10.1093/nar/gkt830
DNA polymerases ζ and Rev1 mediate error-prone bypass of non-B DNA structures
Matthew R. Northam (2014)
10.1101/gr.175547.114
C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency.
B. Meier (2014)
10.1371/journal.pgen.1002223
Global Chromosomal Structural Instability in a Subpopulation of Starving Escherichia coli Cells
D. Lin (2011)
10.1126/science.1199022
DNA Synthesis Generates Terminal Duplications That Seal End-to-End Chromosome Fusions
M. Lowden (2011)
10.1073/pnas.0901710106
Whirly proteins maintain plastid genome stability in Arabidopsis
A. Maréchal (2009)
10.1534/genetics.114.162297
Template Switching During Break-Induced Replication Is Promoted by the Mph1 Helicase in Saccharomyces cerevisiae
Anamarija Štafa (2014)
10.1038/nature09744
The genomic complexity of primary human prostate cancer
M. Berger (2011)
10.1186/gb-2011-12-10-r103
Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer
W. Kloosterman (2011)
10.1016/S0074-7696(06)55002-8
Roles of DNA polymerases in replication, repair, and recombination in eukaryotes.
Y. Pavlov (2006)
10.1101/gr.143677.112
Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms.
A. Malhotra (2013)
10.1016/j.cell.2011.07.042
Chromosome Catastrophes Involve Replication Mechanisms Generating Complex Genomic Rearrangements
P. Liu (2011)
10.1101/gr.115782.110
RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology.
A. Lawson (2011)
10.1093/nar/gks948
A four-subunit DNA polymerase ζ complex containing Pol δ accessory subunits is essential for PCNA-mediated mutagenesis
A. V. Makarova (2012)
recombination-coupled DNA synthesis via bubble migration. Nature
S. A. Yatsenko (2012)
10.1038/ng.2768
Replicative mechanisms for CNV formation are error prone
C. Carvalho (2013)
10.1128/MCB.01469-08
Aberrant Double-Strand Break Repair Resulting in Half Crossovers in Mutants Defective for Rad51 or the DNA Polymerase δ Complex
C. E. Smith (2009)
10.1101/gad.250258.114
Chromosome rearrangements via template switching between diverged repeated sequences.
R. Anand (2014)
10.1371/journal.pgen.1004119
Cascades of Genetic Instability Resulting from Compromised Break-Induced Replication
Soumini Vasan (2014)
10.1016/j.celrep.2012.05.009
Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms.
W. Kloosterman (2012)
10.1158/1541-7786.MCR-04-0194
The Loss of a Single Telomere Can Result in Instability of Multiple Chromosomes in a Human Tumor Cell Line
L. Sabatier (2005)
10.1093/hmg/ddr073
Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline.
W. Kloosterman (2011)
10.1371/journal.pgen.0020048
On the Mechanism of Gene Amplification Induced under Stress in Escherichia coli
A. Slack (2006)
10.1371/journal.pgen.1000475
The Yeast Pif1 Helicase Prevents Genomic Instability Caused by G-Quadruplex-Forming CEB1 Sequences In Vivo
Cyril Ribeyre (2009)
10.1038/nature12585
Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration
M. Wilson (2013)
10.1007/s00439-015-1539-4
Characterization of 26 deletion CNVs reveals the frequent occurrence of micro-mutations within the breakpoint-flanking regions and frequent repair of double-strand breaks by templated insertions derived from remote genomic regions
Ye Wang (2015)



This paper is referenced by
10.1101/254631
Thermodynamic analysis of mitochondrial DNA breakpoints reveals mechanistic details of deletion mutagenesis
L. N. Lakshmanan (2018)
10.1016/j.tig.2018.04.002
Break-Induced Replication: The Where, The Why, and The How.
J. Kramara (2018)
10.1101/GAD.288142.116
Replication fork instability and the consequences of fork collisions from rereplication.
Jessica L. Alexander (2016)
10.1016/j.cell.2019.01.045
Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2
C. Beck (2019)
10.1101/2020.02.28.969154
Mechanisms preventing Break-Induced Replication during repair of two-ended DNA double-strand breaks
N. Pham (2020)
10.1093/nar/gkz651
Repair of base damage within break-induced replication intermediates promotes kataegis associated with chromosome rearrangements
R. Elango (2019)
10.1016/j.celrep.2017.10.079
Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication.
O. Buzovetsky (2017)
10.3390/genes11020224
Yeast Genome Maintenance by the Multifunctional PIF1 DNA Helicase Family
Julius Muellner (2020)
10.3390/biology6040042
Living Organisms Author Their Read-Write Genomes in Evolution
J. Shapiro (2017)
10.1038/nature24477
Mechanism of tandem duplication formation in BRCA1 mutant cells
Nicholas A. Willis (2017)
10.3390/genes10110901
Mitotic Recombination and Adaptive Genomic Changes in Human Pathogenic Fungi
A. Gusa (2019)
10.1016/bs.mie.2017.12.010
Investigation of Break-Induced Replication in Yeast.
R. Elango (2018)
10.1038/s12276-018-0112-3
Patterns and mechanisms of structural variations in human cancer
Kijong Yi (2018)
10.17863/CAM.22674
Patterns of somatic genome rearrangement in human cancer
Nicola D. Roberts (2018)
Within genome variation of germ-line and somatic mutation
Thomas C A Smith (2017)
10.1038/s41580-019-0152-0
DNA double-strand break repair-pathway choice in somatic mammalian cells
R. Scully (2019)
10.17077/etd.ia2vsjmb
Break-induced replication repair pathway promotes mutagenesis and genomic instability in Saccharomyces cerevisiae
R. Elango (2017)
10.1371/journal.pgen.1007995
What is mutation? A chapter in the series: How microbes “jeopardize” the modern synthesis
D. Fitzgerald (2019)
10.1371/journal.pgen.1006446
Mechanisms for Complex Chromosomal Insertions
Shen Gu (2016)
10.1093/nar/gkz705
DNA polymerase ζ in DNA replication and repair
S. K. Martin (2019)
10.1109/ICCABS.2017.8114297
Concurrent MMBIRFinder
T. Alsulaiman (2017)
10.1016/j.dnarep.2020.102868
Hypermutation in single-stranded DNA
N. Saini (2020)
10.1007/s00294-018-0822-z
Chromosome ends as adaptive beginnings: the potential role of dysfunctional telomeres in subtelomeric evolvability
Jennifer M O Mason (2018)
10.1146/ANNUREV-GENET-120215-035243
Eukaryotic DNA Polymerases in Homologous Recombination.
M. McVey (2016)
10.1101/gr.214973.116
Short template switch events explain mutation clusters in the human genome.
A. Löytynoja (2017)
10.1016/j.mrrev.2017.04.002
Interstitial telomeric sequences in vertebrate chromosomes: Origin, function, instability and evolution.
A. Bolzán (2017)
10.1038/nsmb.3334
The role of break-induced replication in large-scale expansions of (CAG)n•(CTG)n repeats
Jane C. Kim (2017)
10.1371/journal.pgen.1006714
Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions
S. Sinha (2017)
10.4172/2168-975X.1000217
Significance of Interviral Recombination as Novel Mechanism for Extending Viral Disease Repertoire
E. Johnson (2016)
Essential Roles for Polymerase Theta-Mediated End Joining in Repair of Chromosome Breaks
D. Wyatt (2017)
Molecular mechanisms and signaling pathways involved in genome stability in the human fungal pathogen, Candida albicans
Adeline Feri (2016)
10.1242/jcs.238709
Translesion synthesis polymerases contribute to meiotic chromosome segregation and cohesin dynamics in Schizosaccharomyces pombe
T. Mastro (2020)
See more
Semantic Scholar Logo Some data provided by SemanticScholar