Cascades of Genetic Instability Resulting from Compromised Break-Induced Replication

Break-induced replication (BIR) is a mechanism to repair double-strand breaks (DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities including mutations, loss of heterozygosity, deletions, duplications, and template switching that can result in copy-number variations (CNVs). An important type of genomic rearrangement specifically linked to BIR is half-crossovers (HCs), which result from fusions between parts of recombining chromosomes. Because HC formation produces a fused molecule as well as a broken chromosome fragment, these events could be highly destabilizing. Here we demonstrate that HC formation results from the interruption of BIR caused by a damaged template, defective replisome or premature onset of mitosis. Additionally, we document that checkpoint failure promotes channeling of BIR into half-crossover-initiated instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. We postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer.

[1]  Anna Malkova,et al.  Migrating bubble during break-induced replication drives conservative DNA synthesis , 2013, Nature.

[2]  Anna Malkova,et al.  Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration , 2013, Nature.

[3]  L. Symington,et al.  Break-induced replication occurs by conservative DNA synthesis , 2013, Proceedings of the National Academy of Sciences.

[4]  A. Malkova,et al.  Break-induced replication: functions and molecular mechanism. , 2013, Current opinion in genetics & development.

[5]  Hengshan Zhang,et al.  Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae , 2013, Genetics.

[6]  J. Haber,et al.  Mutations arising during repair of chromosome breaks. , 2012, Annual review of genetics.

[7]  Cynthia J. Sakofsky,et al.  Break-Induced Replication and Genome Stability , 2012, Biomolecules.

[8]  Xuewen Pan,et al.  The Fun30 ATP-dependent nucleosome remodeler promotes resection of DNA double-strand break ends , 2012, Nature.

[9]  A. Aguilera,et al.  Complex Chromosomal Rearrangements Mediated by Break-Induced Replication Involve Structure-Selective Endonucleases , 2012, PLoS genetics.

[10]  R. Kolodner,et al.  A Genetic and Structural Study of Genome Rearrangements Mediated by High Copy Repeat Ty1 Elements , 2011, PLoS genetics.

[11]  A. Malkova,et al.  Break-Induced Replication Is Highly Inaccurate , 2011, PLoS biology.

[12]  Maitreya J. Dunham,et al.  Competitive Repair by Naturally Dispersed Repetitive DNA during Non-Allelic Homologous Recombination , 2010, PLoS genetics.

[13]  Bruce Stillman,et al.  Break-induced replication requires all essential DNA replication factors except those specific for pre-RC assembly. , 2010, Genes & development.

[14]  A. Malkova,et al.  Defective Resection at DNA Double-Strand Breaks Leads to De Novo Telomere Formation and Enhances Gene Targeting , 2010, PLoS genetics.

[15]  T. Halazonetis,et al.  Genomic instability — an evolving hallmark of cancer , 2010, Nature Reviews Molecular Cell Biology.

[16]  J. Lupski,et al.  Mechanisms of change in gene copy number , 2009, Nature Reviews Genetics.

[17]  J. Haber,et al.  A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair. , 2009, Genes & development.

[18]  L. Symington,et al.  Aberrant Double-Strand Break Repair Resulting in Half Crossovers in Mutants Defective for Rad51 or the DNA Polymerase δ Complex , 2009, Molecular and Cellular Biology.

[19]  J. Lupski,et al.  A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation , 2009, PLoS genetics.

[20]  S. Jackson,et al.  DNA helicases Sgs1 and BLM promote DNA double-strand break resection. , 2008, Genes & development.

[21]  A. Malkova,et al.  Large inverted repeats in the vicinity of a single double-strand break strongly affect repair in yeast diploids lacking Rad51. , 2008, Mutation research.

[22]  Eleni P. Mimitou,et al.  Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing , 2008, Nature.

[23]  E. Koonin,et al.  X-ray structure of the complex of regulatory subunits of human DNA polymerase delta , 2008, Cell cycle.

[24]  G. Ira,et al.  Sgs1 Helicase and Two Nucleases Dna2 and Exo1 Resect DNA Double-Strand Break Ends , 2008, Cell.

[25]  Romain Koszul,et al.  Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms , 2008, PLoS genetics.

[26]  P. Mieczkowski,et al.  Double-strand breaks associated with repetitive DNA can reshape the genome , 2008, Proceedings of the National Academy of Sciences.

[27]  A. Malkova,et al.  Defective Break-Induced Replication Leads to Half-Crossovers in Saccharomyces cerevisiae , 2008, Genetics.

[28]  P. Sung,et al.  Mechanism of eukaryotic homologous recombination. , 2008, Annual review of biochemistry.

[29]  J. Haber,et al.  Mechanisms of Rad52-Independent Spontaneous and UV-Induced Mitotic Recombination in Saccharomyces cerevisiae , 2008, Genetics.

[30]  David Lydall,et al.  Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeres , 2008, The EMBO journal.

[31]  L. Symington,et al.  Break-induced replication: What is it and what is it for? , 2008, Cell cycle.

[32]  Jiri Bartek,et al.  An Oncogene-Induced DNA Damage Model for Cancer Development , 2008, Science.

[33]  D. Gordenin,et al.  Apn1 and Apn2 endonucleases prevent accumulation of repair-associated DNA breaks in budding yeast as revealed by direct chromosomal analysis , 2008, Nucleic acids research.

[34]  J. Haber,et al.  Break-induced replication and telomerase-independent telomere maintenance require Pol32 , 2007, Nature.

[35]  T. Petes,et al.  Inverted DNA Repeats Channel Repair of Distant Double-Strand Breaks into Chromatid Fusions and Chromosomal Rearrangements , 2007, Molecular and Cellular Biology.

[36]  James E Haber,et al.  Surviving the breakup: the DNA damage checkpoint. , 2006, Annual review of genetics.

[37]  M. Wyatt,et al.  Methylating agents and DNA repair responses: Methylated bases and sources of strand breaks. , 2006, Chemical research in toxicology.

[38]  J. Kingsbury,et al.  Role of Nitrogen and Carbon Transport, Regulation, and Metabolism Genes for Saccharomyces cerevisiae Survival In Vivo , 2006, Eukaryotic Cell.

[39]  T. Petes,et al.  Chromosomal Translocations in Yeast Induced by Low Levels of DNA Polymerase A Model for Chromosome Fragile Sites , 2005, Cell.

[40]  J. Murnane,et al.  The Loss of a Single Telomere Can Result in Instability of Multiple Chromosomes in a Human Tumor Cell Line , 2005, Molecular Cancer Research.

[41]  J. Haber,et al.  RAD51-Dependent Break-Induced Replication Differs in Kinetics and Checkpoint Responses from RAD51-Mediated Gene Conversion , 2005, Molecular and Cellular Biology.

[42]  D. Gottschling,et al.  An Age-Induced Switch to a Hyper-Recombinational State , 2003, Science.

[43]  T. Kunkel,et al.  In Vivo Consequences of Putative Active Site Mutations in Yeast DNA Polymerases α, ε, δ, and ζ , 2001 .

[44]  J. Haber,et al.  Multiple Pathways of Recombination Induced by Double-Strand Breaks in Saccharomyces cerevisiae , 1999, Microbiology and Molecular Biology Reviews.

[45]  J. Haber,et al.  Double-Strand Break Repair in Yeast Requires Both Leading and Lagging Strand DNA Polymerases , 1999, Cell.

[46]  D. Gordenin,et al.  Destabilization of Yeast Micro- and Minisatellite DNA Sequences by Mutations Affecting a Nuclease Involved in Okazaki Fragment Processing (rad27) and DNA Polymerase δ (pol3-t) , 1998, Molecular and Cellular Biology.

[47]  C. Connelly,et al.  "Break copy" duplication: a model for chromosome fragment formation in Saccharomyces cerevisiae. , 1997, Genetics.

[48]  J. Haber,et al.  Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  P. Philippsen,et al.  New heterologous modules for classical or PCR‐based gene disruptions in Saccharomyces cerevisiae , 1994, Yeast.

[50]  D. Gordenin,et al.  Transposon Tn5 excision in yeast: influence of DNA polymerases alpha, delta, and epsilon and repair genes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. Hamatake,et al.  A third essential DNA polymerase in S. cerevisiae , 1990, Cell.

[52]  G. Lucchini,et al.  DNA polymerase I gene of Saccharomyces cerevisiae: nucleotide sequence, mapping of a temperature-sensitive mutation, and protein homology with other DNA polymerases. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[53]  J. Haber,et al.  Rad52-independent mitotic gene conversion in Saccharomyces cerevisiae frequently results in chromosomal loss. , 1985, Genetics.

[54]  T. Kunkel,et al.  In vivo consequences of putative active site mutations in yeast DNA polymerases alpha, epsilon, delta, and zeta. , 2001, Genetics.

[55]  J. Grisham,et al.  Effects of 4-nitroquinoline-1-oxide on population growth, cell-cycle compartmentalization and viability in human lymphoblastoid cells. , 1991, Toxicology in vitro : an international journal published in association with BIBRA.

[56]  Janina Maier,et al.  Guide to yeast genetics and molecular biology. , 1991, Methods in enzymology.