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

Topoisomerase II– And Condensin-Dependent Breakage Of MEC1ATR-Sensitive Fragile Sites Occurs Independently Of Spindle Tension, Anaphase, Or Cytokinesis

Nadia Hashash, A. L. Johnson, R. Cha
Published 2012 · Biology, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
Fragile sites are loci of recurrent chromosome breakage in the genome. They are found in organisms ranging from bacteria to humans and are implicated in genome instability, evolution, and cancer. In budding yeast, inactivation of Mec1, a homolog of mammalian ATR, leads to chromosome breakage at fragile sites referred to as replication slow zones (RSZs). RSZs are proposed to be homologous to mammalian common fragile sites (CFSs) whose stability is regulated by ATR. Perturbation during S phase, leading to elevated levels of stalled replication forks, is necessary but not sufficient for chromosome breakage at RSZs or CFSs. To address the nature of additional event(s) required for the break formation, we examined involvement of the currently known or implicated mechanisms of endogenous chromosome breakage, including errors in replication fork restart, premature mitotic chromosome condensation, spindle tension, anaphase, and cytokinesis. Results revealed that chromosome breakage at RSZs is independent of the RAD52 epistasis group genes and of TOP3, SGS1, SRS2, MMS4, or MUS81, indicating that homologous recombination and other recombination-related processes associated with replication fork restart are unlikely to be involved. We also found spindle force, anaphase, or cytokinesis to be dispensable. RSZ breakage, however, required genes encoding condensin subunits (YCG1, YSC4) and topoisomerase II (TOP2). We propose that chromosome break formation at RSZs following Mec1 inactivation, a model for mammalian fragile site breakage, is mediated by internal chromosomal stress generated during mitotic chromosome condensation.
This paper references
10.1016/j.cell.2008.01.035
Phosphorylation of the Axial Element Protein Hop1 by Mec1/Tel1 Ensures Meiotic Interhomolog Recombination
Jesús A. Carballo (2008)
10.1038/35003501
The importance of repairing stalled replication forks
M. Cox (2000)
10.1007/BF00295030
Rodent common fragile sites: Are they conserved? Evidence from mouse and rat
F. B. Elder (2004)
10.1016/S0092-8674(00)81211-8
An ESP1/PDS1 Complex Regulates Loss of Sister Chromatid Cohesion at the Metaphase to Anaphase Transition in Yeast
R. Ciosk (1998)
DNA topoisomerase II is required for condensation and separation of mitotic chromosomes
T Uemura (1987)
A direct link between sister chromtid cohesion and chromosome condensation revealed through the analysis of MCD1 in S
V Guacci (1997)
Induction of sister chromatid exchanges at common fragile sites.
T. Glover (1987)
10.1073/PNAS.81.9.2616
DNA topoisomerase II mutant of Saccharomyces cerevisiae: topoisomerase II is required for segregation of daughter molecules at the termination of DNA replication.
S. Dinardo (1984)
Fragile sites on human chromosomes. New York: Oxford University Press. Mechanism of Fragile Site Breakage PLOS Genetics | www.plosgenetics.org 9 October
G Sutherland (1985)
10.1016/S0092-8674(00)00063-5
swi1 and swi3 Perform Imprinting, Pausing, and Termination of DNA Replication in S. pombe
J. Dalgaard (2000)
10.1007/s00412-007-0138-0
Beyond the code: the mechanical properties of DNA as they relate to mitosis
K. Bloom (2007)
10.1016/S0092-8674(00)00130-6
Cleavage of Cohesin by the CD Clan Protease Separin Triggers Anaphase in Yeast
F. Uhlmann (2000)
10.1093/emboj/cdf369
Replication fork collapse at replication terminator sequences
V. Bidnenko (2002)
10.1073/PNAS.0506497102
Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites.
Eliane El Achkar (2005)
10.1016/j.molcel.2008.08.025
Mus81-dependent double-strand DNA breaks at in vivo-generated cruciform structures in S. cerevisiae.
Atina G. Coté (2008)
10.1091/MBC.E06-05-0454
In vivo analysis of chromosome condensation in Saccharomyces cerevisiae.
A. C. Vas (2007)
10.1101/GAD.249202
Cohesin release is required for sister chromatid resolution, but not for condensin-mediated compaction, at the onset of mitosis.
A. Losada (2002)
10.1016/j.cell.2009.06.022
Genome-Organizing Factors Top2 and Hmo1 Prevent Chromosome Fragility at Sites of S phase Transcription
Rodrigo Bermejo (2009)
10.1083/JCB.125.3.517
Chromosome condensation and sister chromatid pairing in budding yeast
V. Guacci (1994)
10.1016/j.cell.2005.03.022
Gross Chromosomal Rearrangements and Elevated Recombination at an Inducible Site-Specific Replication Fork Barrier
S. Lambert (2005)
10.1038/ncb1883
The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities
V. Naim (2009)
10.1534/genetics.109.107508
Centromere Replication Timing Determines Different Forms of Genomic Instability in Saccharomyces cerevisiae Checkpoint Mutants During Replication Stress
W. Feng (2009)
10.1016/0165-4608(85)90202-X
Chromosome fragile sites.
F. E. Yoder (1985)
10.1016/j.cell.2011.08.032
Regulatory Control of the Resolution of DNA Recombination Intermediates during Meiosis and Mitosis
J. Matos (2011)
10.1126/science.170.3953.85
Heritable Fragile Site on Chromosome 16: Probable Localization of Haptoglobin Locus in Man
R. Magenis (1970)
10.1016/S0092-8674(02)01113-3
ATR Regulates Fragile Site Stability
A. Casper (2002)
10.1126/SCIENCE.290.5492.806
Direct coupling between meiotic DNA replication and recombination initiation.
V. Borde (2000)
10.1083/JCB.142.5.1301
Involvement of an Actomyosin Contractile Ring in Saccharomyces cerevisiae Cytokinesis
E. Bi (1998)
10.1534/g3.111.000554
Replication Stress-Induced Chromosome Breakage Is Correlated with Replication Fork Progression and Is Preceded by Single-Stranded DNA Formation
W. Feng (2011)
Features of the chromosome terminus region In: Neidhardt F, editor. Escherichia coli and Salmonella: Cellular and Molecular Biology
T Hill (1996)
10.1242/jcs.077313
Regulation of fragile sites expression in budding yeast by MEC1, RRM3 and hydroxyurea
Nadia Hashash (2011)
10.1073/PNAS.95.14.8141
Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site.
D. Mishmar (1998)
10.1093/nar/gkq552
The ribonucleotide reductase inhibitor, Sml1, is sequentially phosphorylated, ubiquitylated and degraded in response to DNA damage
Bethany L. Andreson (2010)
The DNA replication checkpoint response stablizes stalled replication
M Lopes (2001)
10.1038/ncb1882
Replication stress induces sister-chromatid bridging at fragile site loci in mitosis
K. L. Chan (2009)
10.1101/GAD.1320505
Dynamic molecular linkers of the genome: the first decade of SMC proteins.
A. Losada (2005)
10.1016/S0092-8674(01)80008-8
A Direct Link between Sister Chromatid Cohesion and Chromosome Condensation Revealed through the Analysis of MCD1 in S. cerevisiae
V. Guacci (1997)
10.1016/0168-9525(87)90268-X
Fragile sites in human chromosomes as regions of late-replicating DNA
C. Laird (1987)
10.1016/j.molcel.2008.04.019
Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast.
J. Baxter (2008)
10.1159/000132885
Common fragile sites in man and three closely related primate species.
D. Smeets (1990)
10.1083/JCB.131.1.7
A postprophase topoisomerase II-dependent chromatid core separation step in the formation of metaphase chromosomes
J. Giménez-Abián (1995)
10.1038/35087613
The DNA replication checkpoint response stabilizes stalled replication forks
M. Lopes (2001)
10.1016/S0921-8777(01)00091-X
DNA postreplication repair and mutagenesis in Saccharomyces cerevisiae.
S. Broomfield (2001)
10.1038/nature05649
Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map
S. Collins (2007)
10.1007/s10577-007-1145-y
Meiotic roles of Mec1, a budding yeast homolog of mammalian ATR/ATM
Jesús A. Carballo (2007)
10.1083/jcb.200412076
The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress
Jeff Bachant (2005)
10.1101/GAD.12.18.2956
Recovery from DNA replicational stress is the essential function of the S-phase checkpoint pathway.
B. Desany (1998)
10.1128/MCB.14.2.1465
Nature and distribution of chromosomal intertwinings in Saccharomyces cerevisiae.
R. M. Spell (1994)
10.1016/J.MOLCEL.2004.11.001
DNA replication checkpoint prevents precocious chromosome segregation by regulating spindle behavior.
Vaidehi Krishnan (2004)
10.1007/BF00272988
DNA polymerase α inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes
T. Glover (2004)
10.1126/SCIENCE.1071398
ATR Homolog Mec1 Promotes Fork Progression, Thus Averting Breaks in Replication Slow Zones
R. Cha (2002)
10.1093/NAR/22.15.3104
An essential gene, ESR1, is required for mitotic cell growth, DNA repair and meiotic recombination in Saccharomyces cerevisiae.
R. Kato (1994)
10.1016/0092-8674(87)90518-6
DNA topoisomerase II is required for condensation and separation of mitotic chromosomes in S. pombe
Tadashi Uemura (1987)
Features of the chromosome terminus region
T Hill (1996)
A (2005) Gross chromosomal rearrangements and elevated recombination at an inducible site-specific recombination fork barrier
S Lambert (2005)
10.1371/journal.pgen.1000015
DNA Damage Activates the SAC in an ATM/ATR-Dependent Manner, Independently of the Kinetochore
E. Kim (2008)
10.1101/GAD.1392506
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)
10.1016/S0092-8674(02)00614-1
The Mre11 Complex Is Required for Repair of Hairpin-Capped Double-Strand Breaks and Prevention of Chromosome Rearrangements
K. Lobachev (2002)
10.1101/GAD.8.6.652
Mitotic checkpoint genes in budding yeast and the dependence of mitosis on DNA replication and repair.
T. Weinert (1994)
10.1146/ANNUREV.GENET.37.042203.120656
The spindle assembly and spindle position checkpoints.
D. Lew (2003)
10.1007/s004120000065
Premitotic chromosome individualization in mammalian cells depends on topoisomerase II activity
J. Giménez‐Abián (2000)
10.1016/s0031-3025(16)38490-2
Fragile sites on human chromosomes
G. Sutherland (1985)
10.1091/MBC.11.4.1293
Mitotic chromosome condensation requires Brn1p, the yeast homologue of Barren.
B. D. Lavoie (2000)
10.1103/PHYSREVLETT.74.4754
Stretching DNA with a receding meniscus: Experiments and models.
Bensimon (1995)
10.1016/S1097-2765(00)80277-4
A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools.
X. Zhao (1998)
10.1101/GAD.14.4.493
Progression of meiotic DNA replication is modulated by interchromosomal interaction proteins, negatively by Spo11p and positively by Rec8p.
R. Cha (2000)
10.1083/jcb.200109056
In vivo dissection of the chromosome condensation machinery
B. D. Lavoie (2002)
10.1038/sj.onc.1210849
Interplay between ATM and ATR in the regulation of common fragile site stability
E. Ozeri-Galai (2008)
10.1101/GAD.1154704
Local chromatin structure at the ribosomal DNA causes replication fork pausing and genome instability in the absence of the S. cerevisiae DNA helicase Rrm3p.
J. Torres (2004)
10.1016/j.molcel.2010.07.015
Homologous recombination restarts blocked replication forks at the expense of genome rearrangements by template exchange.
S. Lambert (2010)
10.1093/emboj/20.13.3544
The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage
X. Zhao (2001)
10.1038/35087607
Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint
J. Tercero (2001)
10.1101/GAD.9.5.587
SMC2, a Saccharomyces cerevisiae gene essential for chromosome segregation and condensation, defines a subgroup within the SMC family.
A. Strunnikov (1995)
10.1093/emboj/18.10.2707
Sister chromatid separation and chromosome re‐duplication are regulated by different mechanisms in response to spindle damage
G. Alexandru (1999)
10.1016/J.MOLCEL.2007.06.012
An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae.
Haihua Zhang (2007)
10.1101/GAD.12.13.1986
Identification of Xenopus SMC protein complexes required for sister chromatid cohesion.
A. Losada (1998)
10.1016/j.cell.2004.12.039
Chromosomal Translocations in Yeast Induced by Low Levels of DNA Polymerase A Model for Chromosome Fragile Sites
Francene J. Lemoine (2005)
10.1101/GAD.340905
Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability.
M. Schwartz (2005)
10.1016/0092-8674(88)90222-X
A replication fork barrier at the 3′ end of yeast ribosomal RNA genes
B. Brewer (1988)



This paper is referenced by
10.1371/journal.pgen.1006277
A Checkpoint-Related Function of the MCM Replicative Helicase Is Required to Avert Accumulation of RNA:DNA Hybrids during S-phase and Ensuing DSBs during G2/M
Sriram Vijayraghavan (2016)
10.1007/s00018-017-2474-4
S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion
M. Giannattasio (2017)
10.2174/1389202916666150114223205
DNA Secondary Structure at Chromosomal Fragile Sites in Human Disease
Ryan G. Thys (2015)
10.1242/bio.015347
S phase block following MEC1ATR inactivation occurs without severe dNTP depletion
Caroline Earp (2015)
BIO015347 1739..1743
Caroline Earp (2015)
Regulation of genome stability via Mcm2-7 ATPase active sites in Saccharomyces cerevisiae
Sriram Vijayraghavan (2014)
10.1007/s00412-013-0398-9
Impediments to replication fork movement: stabilisation, reactivation and genome instability
S. Lambert (2013)
10.1016/j.cell.2014.05.046
ATR Mediates a Checkpoint at the Nuclear Envelope in Response to Mechanical Stress
Amit Kumar (2014)
10.1101/2020.09.17.301317
Topoisomerase II deficiency leads to a postreplicative structural shift in all Saccharomyces cerevisiae chromosomes
Jessel Ayra-Plasencia (2020)
10.3390/genes8020049
Regulation of Replication Fork Advance and Stability by Nucleosome Assembly
F. Prado (2017)
10.1016/j.bcp.2014.09.006
Yeast cytotoxic sensitivity to the antitumour agent β-lapachone depends mainly on oxidative stress and is largely independent of microtubule- or topoisomerase-mediated DNA damage.
C. Ramos-Pérez (2014)
10.1080/15384101.2016.1274585
Not all roads lead to Cdk1
D. Branzei (2017)
Causes of Genome Instability
Centro Andaluz de BiologMolecular (2013)
10.1002/em.21859
Mechanisms of chromosomal instability in melanoma
W. Kaufmann (2014)
10.1101/cshperspect.a015792
Chromosome Dynamics during Mitosis.
T. Hirano (2015)
10.13130/niska-joanna_phd2014-03-25
TERMINATING REPLICATION AT TERS AT EUKARYOTIC CHROMOSOMES
J. Niska (2014)
10.7554/eLife.42955
Genetic analysis reveals functions of atypical polyubiquitin chains
Fernando Meza Gutierrez (2018)
10.1101/644443
Two different pathways for initiation of Trichoderma reesei Rad51-only meiotic recombination
W. Li (2019)
10.1016/j.semcancer.2018.04.005
DNA replication stress and its impact on chromosome segregation and tumorigenesis.
B. N. Zhang (2019)
10.1038/s41467-020-18580-9
ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration
G. R. Kidiyoor (2020)
10.1101/508713
Common fragile sites are characterised by faulty condensin loading after replication stress
L. Boteva (2020)
10.1371/journal.pgen.1003931
Recombinogenic Conditions Influence Partner Choice in Spontaneous Mitotic Recombination
J. Cauwood (2013)
10.1002/path.4823
MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer
Y. Sun (2017)
10.1016/j.celrep.2020.108177
Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress
L. Boteva (2020)
10.1007/s00018-014-1717-x
Are common fragile sites merely structural domains or highly organized “functional” units susceptible to oncogenic stress?
A. Georgakilas (2014)
10.1146/annurev-genet-111212-133232
Causes of genome instability.
A. Aguilera (2013)
Semantic Scholar Logo Some data provided by SemanticScholar