Leaping forks at inverted repeats
Dana Branzei1,4and Marco Foiani1,2,3
1Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy;
Biotecnologie, Universita ` Degli Studi di Milano, 20133 Milan, Italy
2Dipartimento di Scienze Biomolecolari e
Genome rearrangements are often associated with ge-
nome instability observed in cancer and other patho-
logical disorders. Different types of repeat elements
are common in genomes and are prone to instability.
S-phase checkpoints, recombination, and telomere main-
tenance pathways have been implicated in suppressing
chromosome rearrangements, but little is known about
the molecular mechanisms and the chromosome in-
termediates generating such genome-wide instability. In
the December 15, 2009, issue of Genes & Development,
two studies by Paek and colleagues (2861–2875) and
Mizuno and colleagues (pp. 2876–2886), demonstrate that
nearby inverted repeats in budding and fission yeasts
recombine spontaneously and frequently to form di-
centric and acentric chromosomes. The recombination
mechanism underlying this phenomenon does not appear
to require double-strand break formation, and is likely
caused by a replication mechanism involving template
Maintaining genome stability is crucial for normal cell
growth, as revealed by the fact that many cancers and
numerous genetic diseases are associated with genome
rearrangements (Kolodner et al. 2002). The molecular
mechanisms underlying such large-scale chromosome
changes, often referred to as gross chromosomal rear-
rangements (GCRs), are complex. Genetic studies, con-
ducted mostly in the budding yeast Saccharomyces
cerevisiae, have helped to identify numerous genes and
pathways suppressing such alterations. Many of these
have established functions in monitoring the integrity of
replication forks (S-phase checkpoints) or in mediating
genetic exchanges by means of homologous recombina-
tion (HR), an important genome integrity mechanism
promoting the repair of double-strand breaks (DSBs) or
single-strand gaps formed during replication or arising
from processing DNA-damaging lesions. At-risk DNA
elements have been identified in the genome: They
contain different types of repeat sequences that are prone
to instability and influence the rate of genome rearrange-
ments (Gordenin and Resnick 1998).
Several lines of evidence led to the common view that
GCR formation is initiated by replication dysfunction.
Accordingly, mutations in genes encoding DNA replica-
tion proteins or S-phase checkpoint components, or
causing dysregulation of replication origins result in
genome instability and increased GCR rates (Chen and
Kolodner 1999; Myung et al. 2001; Lengronne and
Schwob 2002). The DNA structures arising during DNA
replication that are processed to yield genome rearrange-
ments are not yet clear, but DSBs have been proposed to
mediate many of them. In the December 15, 2009, issue
of Genes & Development, two studies by Paek et al.
(2009) and Mizuno et al. (2009) uncover novel replication-
based mechanisms that likely do not involve a DSB
intermediate, and that operate at nearby inverted repeats
to generate dicentric chromosome intermediates that,
upon segregation, lead to breakage and further chromo-
Inverted repeats, palindromes, and dicentric
Repetitive elements are abundant in genomes, and fre-
quently serve as substrates for genome rearrangements
(Batzer and Deininger 2002). The biological basis for this
extends beyond the high density of these elements and is
explained by their ability to disrupt DNA replication and
essential repair processes. For instance, simple repeat
sequences located within a short distance of each other
are prone to replication errors, leading to small deletion
and duplication mutations. Repetitive DNA sequences
also induce recombination. Not surprisingly, therefore,
low-copy repeats (LCRs) were found to commonly flank
rearranged genomic segments associated with recurrent
genomic rearrangements found in genomic disorders
(Stankiewicz and Lupski 2002). Such rearrangements are
most often mediated by nonallelic HR (NAHR), a mech-
anism of ectopic HR between highly homologous but
nonallelic LCR substrates (Stankiewicz and Lupski 2002).
While recombination between direct repeats results in
deletion and/or duplication of the genomic segment
flanked by the LCRs, recombination between inverted
repeats can invert the intervening sequence (Inoue and
Inverted repeats can be separated by a few base pairs to
many kilobases of DNA. Palindromes—a specific type of
[Keywords: Inverted repeat; breakage–fusion–bridge
instability; template switch; recombination]
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GENES & DEVELOPMENT 24:5–9 ? 2010 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/10; www.genesdev.org5
inverted repeat separated by only very few base pairs—are
poorly tolerated in Escherichia coli cells and are un-
derrepresented in the S. cerevisiae and human genomes
(Lobachev et al. 2000; Stenger et al. 2001), presumably
due to their tendency to form hairpin and cruciform
structures (Lobachev et al. 2002; Lemoine et al. 2005),
which could be recognized and cleaved by a nuclease
(Leach and Stahl 1983) or could affect or slow down DNA
replication (Ahmed and Podemski 1998). Studies in bud-
ding yeast have shown that palindromes can rearrange to
form acentric or dicentric chromosomes (Narayanan
et al. 2006; Voineagu et al. 2008), a finding confirmed in
fission yeast by a recent study (Mizuno et al. 2009).
Acentric and dicentric chromosomes are unstable chro-
mosome intermediates: Acentric palindromic chromo-
somes have been proposed to be precursors for extrachro-
mosomal elements. The two centromeres of a dicentric
chromosome are pulled apart at anaphase to separate
nuclei, causing breakage of the dicentric and the pro-
duction of new ends that fuse to form a new dicentric
chromosome, thus establishing a cycle—the breakage–
fusion–bridge cycle (BFB)—that is believed to play a major
part in gene amplification in cancer (Albrecht et al. 2000;
Narayanan et al. 2006; Tanaka and Yao 2009).
In the December 15, 2009, issue of Genes & Develop-
ment, Paek et al. (2009) found that, in budding yeast,
naturally occurring or synthetic inverted repeats sepa-
rated by ;1.3–5.5 kb of DNA and having as few as ;20
base pairs (bp) of homology can fuse to form acentric or
dicentric chromosomes (Paek et al. 2009). This nearby
inverted repeat fusion phenomenon has been reported
previously in bacteria and in fission yeast (Bi and Liu
1996; Albrecht et al. 2000). Since nearby inverted re-
peats separated by a few kilobases of DNA are unlikely
to form cruciform structures as do palindromes, it is
most probable that the mechanisms leading to forma-
tion of dicentric and acentric chromosomes in these
situations are also different. The recent studies by Paek
et al. (2009) and Mizuno et al. (2009) characterized the
factors influencing the formation of acentric and dicen-
tric chromosome intermediates at nearby inverted re-
peats or palindromic loci in budding and fission yeast,
DSBs as important intermediates leading to genome
Previous genetic studies aimed at uncovering the factors
and pathways that keep the genome rearrangements at
very low levels suggested that the majority of rearrange-
ment events are the result of DSB repair processes
(Kolodner et al. 2002).
Studies in budding yeast have shown that ;2% of the
DSBs induced by ionizing radiation that fall within re-
petitive elements give rise to NAHR-mediated chromo-
somal aberrations reshaping the genome, where the two
ends formed by a single DSB at repetitive sequences act
independently in strand invasion reactions involving
the sister chromatid or the homologous chromosomes
(Argueso et al. 2008).
Many of the rearrangements occurring in a genome
have been proposed to be associated with ongoing repli-
cation. Supportive of the idea that replication stress can
be an important source of breaks leading to DNA struc-
tural changes, previous studies that characterized the
mechanisms of GCR increase in S-phase checkpoint
mutants in budding yeast have found that all of the
genome rearrangements in these mutants involved the
deletion of a chromosome end and de novo addition of
a new telomere (Myung et al. 2001). Based on other
findings, a model has emerged that suggests that replica-
tion forks are prone to stall at repetitive elements
(Voineagu et al. 2008, 2009) and collapse in checkpoint
mutants (Lopes et al. 2001; Cha and Kleckner 2002), thus
generating DNA breaks (Cha and Kleckner 2002) that
often become substrates for telomerase, or can be engaged
in break-induced replication (BIR), a HR pathway pro-
posed to restart collapsed forks or repair single DSBs
(McEachern and Haber 2006).
Although BIR is normally faithful, if the broken end
invades a homolog instead of a sister molecule, it can lead
to loss of heterozygozity; however, if it involves homol-
ogous sequences at a different chromosomal position,
then translocation, duplication, or deletion can result.
BIR could also lead to complex chromosomal rearrange-
ments if it involves multiple rounds of strand invasion,
DNA synthesis, and dissociation, especially if these
events occurred within repetitive regions (Narayanan
et al. 2006; Smith et al. 2007). Similar to other HR events,
BIR is normally dependent on homology and HR factors
(McEachern and Haber 2006). However, a new mecha-
nism of BIR involving microhomology-mediated strand
invasion has been proposed to account for those complex
rearrangements without substantial homologous change
(Payen et al. 2008; Hastings et al. 2009). This model
proposes that, following resection, the 39-end ssDNA
derived from the DSB of a collapsed fork can anneal with
any ssDNA template with which it shares microhomol-
ogy and which is located in physical proximity, in a HR
protein-independent manner (Hastings et al. 2009).
Formation of dicentric chromosomes has also been
proposed to occur through several mechanisms involving
the formation of a DSB intermediate that could then be
processed in several alternative ways (Lobachev et al.
2007). Using different approaches and different organ-
isms, the recent studies by Mizuno et al. (2009) and Paek
et al. (2009) come to an astonishingly similar conclusion:
Nearby inverted repeats can fuse to form acentric and
dicentric chromosomes in a replication-dependent man-
ner, but without involving a DSB as an intermediate
(Mizuno et al. 2009; Paek et al. 2009). The factors
implicated in this rearrangement and the main argu-
ments against a DSB intermediate are described below.
Factors and mechanisms implicated in the fusion
of nearby inverted repeats or palindromes
The studies by Mizuno et al. (2009) and Paek et al. (2009)
analyzed the mechanisms through which nearby inverted
repeats lead to GCRs and chromosome instability. In one
Branzei and Foiani
6GENES & DEVELOPMENT
unstable region of the budding yeast chromosome VII
containing nearby inverted repeats. They report that
those inverted repeats first fuse to form a dicentric
chromosome. This is not a site-specific phenomenon, as
such fusion events are shown to occur at other inverted
repeats present at different sites in the yeast genome.
The instability of this locus was shown previously by
Weinert’s group (Admire et al. 2006 to increase when
DNA replication was disrupted, such as in checkpoint
mutants where replication forks stalling at the repeats
fail to be stabilized). In this recent study, Paek et al. (2009)
found that the fusion observed, which led to dicentric
chromosome formation, did not require known DSB re-
pair (HR, nonhomologous end-joining [NHEJ], or single-
strand annealing [SSA] pathways) or replication fork
pathways (post-replication repair [PRR] and BIR factors).
Interestingly, the only factor found to promote fusion was
Srs2, a helicase that removes Rad51 from ssDNA fila-
ments (Krejci et al. 2003; Veaute et al. 2003), suggesting
that regulating Rad51 activity may affect this process.
On the other hand, the experimental system of Mizuno
et al. (2009) uses a construct consisting of two replication
termination sequences (RTS1) placed in inverted orienta-
tion at the ura4+locus in fission yeast (Lambert et al.
2005), and other modifications of this construct creating
a perfect palindrome, a palindrome interrupted by a 14-bp
spacer, and other constructs aimed at assessing the effect
of the orientation and size of the repeat element (RTS1) or
of other factors that may intervene in the replication of
this genomic segment (Mizuno et al. 2009). The RTS1
locus is naturally present into the Schizosaccharomyces
pombe genome, and ensures efficient mating type switch-
ing in fission yeast by imposing replication fork arrest and
regulating the direction of replication (Dalgaard and Klar
2001; Codlin and Dalgaard 2003). Fork arrest at RTS1
requires the Rtf1 protein: In its absence, forks no longer
arrest at RTS1, which is then replicated normally (Lambert
et al. 2005). Thus, the RTS1 sequences used by Mizuno
et al. (2009) offer the means to conditionally and effi-
ciently stall replication forks by attenuating rtf1+tran-
scription. Previous work conducted in Carr’s laboratory
(Lambert et al. 2005) has shown that, in such an exper-
imental system, in the presence of Rtf1, >95% of the forks
arrest at RTS1 and restart in a manner dependent on HR
Mizuno et al. (2009) found that replication fork arrest
within the palindrome causes a high frequency of chro-
mosomal rearrangement in which the inverted repeats
fuse to form acentric and dicentric chromosomes. In
contrast to the situation described by Paek et al. (2009),
the majority of the fusion events are dependent on HR
protein functions (Mizuno et al. 2009). If the initial
pausing within the RTS1 repeats would generate a DSB
intermediate that will then promote fork restart in a HR-
dependent manner, then one would predict that those
DSB intermediates should become visible after inhibition
of the restart events in HR-deficient cells (or both re-
combination and resection-defective strains). However,
strikingly, DSBs are not detectable by pulse field gel
analysis of the molecular species arising during this
chromosomal rearrangement event (Mizuno et al. 2009).
Thus, although the occasional formation of DSBs during
arrest at such elements cannot be ruled out, the evidence
provided by Mizuno et al. (2009) compellingly suggests
that the vast majority of these restart events do not
involve DSBs as intermediates.
Replication-mediated mechanisms for fusion
of nearby inverted repeats
Based on the observation that such fusion events are
stimulated by replication arrest within the repeated
sequence or by replication problems, the two recent
studies (Mizuno et al. 2009; Paek et al. 2009) propose
a replication-based mechanism involving an aberrant
switch of templates (therefore called faulty template
switch mechanisms) to account for the chromosomal
rearrangements observed. These template switch events
are likely triggered by fork stalling and exposure of
ssDNA gaps at the stalled fork. Previously, to account
for complex rearrangements occurring in genome disor-
ders, an aberrant type of template switch mechanism
involving template exchanges between different replica-
tion forks has been proposed. Following stalling of the
lagging replisome—imposed by regions having abundant
Inverted repeats are shown in red, the DNA segment interrupt-
ing the repeats are shown in black, and the newly synthesized
DNA are shown in blue. In A, the DNA segment containing the
inverted repeats (palindrome) adopts a cruciform structure. One
replication fork arrests within the repeat and can invade the one
of the opposite repeat (Mizuno et al. 2009). In B, the nearby
inverted repeats are separated by longer DNA segments, but
chromatin looping can bring these elements into physical
proximity. Slowing down or fork arrest during replication of
the repeat sequence will lead to accumulation of positive
supercoil ahead of the replication fork, and this can induce fork
regression (Olavarrieta et al. 2002). Following reversal of the
four-way junction (Atkinson and McGlynn 2009), one of the
newly synthesized strands containing some segment of one of
the repeat sequences can reanneal (reinvade) to the wrong repeat
sequence, leading to the fusion (joining) of the repeat sequences
(Paek et al. 2009).
Template switch events at nearby inverted repeats.
Template switch mechanisms at inserted repeats
GENES & DEVELOPMENT7
repetitive elements—there is a switch to a nearby tem-
plate at another fork located in proximity (Branzei and
Foiani 2007; Lee et al. 2007).
The model of Mizuno et al. (2009) resembles this
previous one, and the investigators propose that, follow-
ing fork arrest within the repeat, HR proteins promote the
formation of a recombinogenic 39 end that can invade
the opposite repeat located in physical proximity due to
the cruciform conformation that the palindromic sub-
strate under study is prone to adopt (Fig. 1A; Mizuno et al.
2009). This creates the formation of a Holliday junction
intermediate, the resolution of which results in either
fully replicated chromosomes having the original confor-
mation, or acentric and dicentric chromosome formation
(Mizuno et al. 2009).
In the model proposed by Paek et al. (2009), the fork
stalled within the repeats fails to be rescued by pathways
dependent on HR or PRR factors shown previously to be
involved in template switch formation (Branzei et al.
2008; Branzei and Foiani 2009), and undergoes an alter-
nate type of template switch involving fork regression
(Fig. 1B; Atkinson and McGlynn 2009). Reversed forks are
not common replication intermediates occurring at
stalled forks (Sogo et al. 2002), but accumulation of
a positive superhelical strain in front of the stalled fork
can lead to the formation of four-way junctions or re-
versed forks (Postow et al. 2001; Olavarrieta et al. 2002). It
is possible that nearby inverted repeats are involved in
looping events that may form topological barriers, induce
fork arrest, and promote regression of the stalled fork (Fig.
1). If, during this fork regression process, the nascent
chain pairs with the incorrect, nearby sequence with
which it bears some elements of homology (Paek et al.
2009), then when the regressed fork is reversed back, the
nascent chain can reanneal or reinvade the wrong se-
quence, leading to the fusion events observed by Paek
et al. (2009) (Fig. 1).
The protein promoting this pairing event is not yet
known, as theHR factor Rad52, which hasSSA activity, is
not required for the fusion (Paek et al. 2009). However, if
different pathways contribute to the outcome, the in-
dividual role of the distinct factors involved may be
difficult to establish genetically. In vitro, Rad51 inhibits
the SSA activity of Rad52 (Wu et al. 2008). The observa-
tion that Srs2 (in which Rad51 is somewhat up-regulated
by failure to disrupt Rad51 filaments) is required for the
fusion events observed may mirror a possible role for
Rad52 in this process. In the template switch model
proposed by Paek et al. (2009), completion of DNA
replication following this faulty strand annealing leads
to the formation of a dicentric or acentric chromosome.
The models proposed are speculative, but offer a
method of investigating the exact mechanisms and fac-
tors implicated in such deleterious template exchanges.
As large inverted repeats with high sequence homology
are abundant in the human genome (Warburton et al.
2004), and dicentric chromosomes increase the genomic
instability and likely the cancer risk (Tanaka and Yao
2009), characterizing the replication-associated events
and factors implicated in the formation of such chromo-
some intermediates is important also for understanding
the underlying causes of chromosomal rearrangements
characteristic of oncogenic transformation.
We thank all members of our laboratories for helpful discussions.
The work in D.B.’s laboratory is supported by ERC grant 242928
and the Associazione Italiana per la Ricerca sul Cancro. The
work in M.F.’s laboratory is supported by grants from Telethon,
the Associazione Italiana per la Ricerca sul Cancro, and the
Admire A, Shanks L, Danzl N, Wang M, Weier U, Stevens W,
Hunt E, Weinert T. 2006. Cycles of chromosome instability
are associated with a fragile site and are increased by defects
in DNA replication and checkpoint controls in yeast. Genes
& Dev 20: 159–173.
Ahmed A, Podemski L. 1998. Observations on template switch-
ing during DNA replication through long inverted repeats.
Gene 223: 187–194.
Albrecht EB, Hunyady AB, Stark GR, Patterson TE. 2000.
Mechanisms of sod2 gene amplification in Schizosaccharo-
myces pombe. Mol Biol Cell 11: 873–886.
Argueso JL, Westmoreland J, Mieczkowski PA, Gawel M, Petes
TD, Resnick MA. 2008. Double-strand breaks associated
with repetitive DNA can reshape the genome. Proc Natl
Acad Sci 105: 11845–11850.
Atkinson J, McGlynn P. 2009. Replication fork reversal and the
maintenance of genome stability. Nucleic Acids Res 37:
Batzer MA, Deininger PL. 2002. Alu repeats and human geno-
mic diversity. Nat Rev Genet 3: 370–379.
Bi X, Liu LF. 1996. DNA rearrangement mediated by inverted
repeats. Proc Natl Acad Sci 93: 819–823.
Branzei D, Foiani M. 2007. Template switching: From replica-
tion fork repair to genome rearrangements. Cell 131: 1228–
Branzei D, Foiani M. 2009. The checkpoint response to replica-
tion stress. DNA Repair (Amst) 8: 1038–1046.
Branzei D, Vanoli F, Foiani M. 2008. SUMOylation regulates
Rad18-mediated template switch. Nature 456: 915–920.
Cha RS, Kleckner N. 2002. ATR homolog Mec1 promotes fork
progression, thus averting breaks in replication slow zones.
Science 297: 602–606.
Chen C, Kolodner RD. 1999. Gross chromosomal rearrange-
ments in Saccharomyces cerevisiae replication and recom-
bination defective mutants. Nat Genet 23: 81–85.
Codlin S, Dalgaard JZ. 2003. Complex mechanism of site-
specific DNA replication termination in fission yeast. EMBO
J 22: 3431–3440.
Dalgaard JZ, Klar AJ. 2001. A DNA replication-arrest site RTS1
regulates imprinting by determining the direction of repli-
cation at mat1 in S. pombe. Genes & Dev 15: 2060–2068.
Gordenin DA, Resnick MA. 1998. Yeast ARMs (DNA at-risk
motifs) can reveal sources of genome instability. Mutat Res
Hastings PJ, Lupski JR, Rosenberg SM, Ira G. 2009. Mechanisms
of change in gene copy number. Nat Rev Genet 10: 551–564.
Inoue K, Lupski JR. 2002. Molecular mechanisms for genomic
disorders. Annu Rev Genomics Hum Genet 3: 199–242.
Kolodner RD, Putnam CD, Myung K. 2002. Maintenance of
genome stability in Saccharomyces cerevisiae. Science 297:
Branzei and Foiani
8GENES & DEVELOPMENT
Krejci L, Van Komen S, Li Y, Villemain J, Reddy MS, Klein H, Download full-text
Ellenberger T, Sung P. 2003. DNA helicase Srs2 disrupts the
Rad51 presynaptic filament. Nature 423: 305–309.
Lambert S, Watson A, Sheedy DM, Martin B, Carr AM. 2005.
Gross chromosomal rearrangements and elevated recombi-
nation at an inducible site-specific replication fork barrier.
Cell 121: 689–702.
Leach DR, Stahl FW. 1983. Viability of l phages carrying
a perfect palindrome in the absence of recombination nucle-
ases. Nature 305: 448–451.
Lee JA, Carvalho CMB, Lupski JR. 2007. A DNA replication
mechanism for generating nonrecurrent rearrangements as-
sociated with genomic disorders. Cell 131: 1235–1247.
Lemoine FJ, Degtyareva NP, Lobachev K, Petes TD. 2005.
Chromosomal translocations in yeast induced by low levels
of DNA polymerase a model for chromosome fragile sites.
Cell 120: 587–598.
Lengronne A, Schwob E. 2002. The yeast CDK inhibitor Sic1
prevents genomic instability by promoting replication origin
licensing in late G(1). Mol Cell 9: 1067–1078.
Lobachev KS, Stenger JE, Kozyreva OG, Jurka J, Gordenin DA,
Resnick MA. 2000. Inverted Alu repeats unstable in yeast are
excluded from the human genome. EMBO J 19: 3822–3830.
Lobachev KS, Gordenin DA, Resnick MA. 2002. The Mre11
complex is required for repair of hairpin-capped double-
strand breaks and prevention of chromosome rearrange-
ments. Cell 108: 183–193.
Lobachev KS, Rattray A, Narayanan V. 2007. Hairpin- and
cruciform-mediated chromosome breakage: Causes and con-
sequences in eukaryotic cells. Front Biosci 12: 4208–4220.
Lopes M, Cotta-Ramusino C, Pellicioli A, Liberi G, Plevani P,
Muzi-Falconi M, Newlon CS, Foiani M. 2001. The DNA
replication checkpoint response stabilizes stalled replication
forks. Nature 412: 557–561.
McEachern MJ, Haber JE. 2006. Break-induced replication and
recombinational telomere elongation in yeast. Annu Rev
Biochem 75: 111–135.
Mizuno KI, Lambert S, Baldacci G, Murray JM, Carr AM. 2009.
Nearby inverted repeats fuse to generate acentric and di-
centric palindromic chromosomes by a replication template
exchange mechanism. Genes & Dev 23: 2876–2886.
Myung K, Datta A, Kolodner RD. 2001. Suppression of sponta-
neous chromosomal rearrangements by S phase checkpoint
functions in Saccharomyces cerevisiae. Cell 104: 397–408.
Narayanan V, Mieczkowski PA, Kim HM, Petes TD, Lobachev
KS. 2006. The pattern of gene amplification is determined by
the chromosomal location of hairpin-capped breaks. Cell
Olavarrieta L, Martinez-Robles ML, Sogo JM, Stasiak A,
Hernandez P, Krimer DB, Schvartzman JB. 2002. Supercoil-
ing, knotting and replication fork reversal in partially repli-
cated plasmids. Nucleic Acids Res 30: 656–666.
Paek AL, Kaochar S, Jones H, Elezaby A, Shanks L, Weinert T.
2009. Fusion of nearby inverted repeats by a replication-
based mechanism leads to formation of dicentric and acen-
tric chromosomes that cause genome instability in budding
yeast. Genes & Dev 23: 2861–2875.
Payen C, Koszul R, Dujon B, Fischer G. 2008. Segmental
duplications arise from Pol32-dependent repair of broken
forks through two alternative replication-based mechanisms.
PLoS Genet 4: e1000175. doi: 10.1371/journal.pgen.1000175.
Postow L, Crisona NJ, Peter BJ, Hardy CD, Cozzarelli NR. 2001.
Topological challenges to DNA replication: Conformations
at the fork. Proc Natl Acad Sci 98: 8219–8226.
Smith CE, Llorente B, Symington LS. 2007. Template switching
during break-induced replication. Nature 447: 102–105.
Sogo JM, Lopes M, Foiani M. 2002. Fork reversal and ssDNA
accumulation at stalled replication forks owing to check-
point defects. Science 297: 599–602.
Stankiewicz P, Lupski JR. 2002. Molecular-evolutionary mech-
anisms for genomic disorders. Curr Opin Genet Dev 12: 312–
Stenger JE, Lobachev KS, Gordenin D, Darden TA, Jurka J,
Resnick MA. 2001. Biased distribution of inverted and direct
Alus in the human genome: Implications for insertion,
exclusion, and genome stability. Genome Res 11: 12–27.
Tanaka H, Yao MC. 2009. Palindromic gene amplification–an
evolutionarily conserved role for DNA inverted repeats in
the genome. Nat Rev Cancer 9: 216–224.
Veaute X, Jeusset J, Soustelle C, Kowalczykowski SC, Le Cam E,
Fabre F. 2003. The Srs2 helicase prevents recombination by
disrupting Rad51 nucleoprotein filaments. Nature 423: 309–
Voineagu I, Narayanan V, Lobachev KS, Mirkin SM. 2008.
Replication stalling at unstable inverted repeats: Interplay
between DNA hairpins and fork stabilizing proteins. Proc
Natl Acad Sci 105: 9936–9941.
Voineagu I, Surka CF, Shishkin AA, Krasilnikova MM, Mirkin
SM. 2009. Replisome stalling and stabilization at CGG
repeats, which are responsible for chromosomal fragility.
Nat Struct Mol Biol 16: 226–228.
Warburton PE, Giordano J, Cheung F, Gelfand Y, Benson G.
2004. Inverted repeat structure of the human genome: The
X-chromosome contains a preponderance of large, highly
homologous inverted repeats that contain testes genes.
Genome Res 14: 1861–1869.
Wu Y, Kantake N, Sugiyama T, Kowalczykowski SC. 2008.
Rad51 protein controls Rad52-mediated DNA annealing.
J Biol Chem 283: 14883–14892.
Template switch mechanisms at inserted repeats
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