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Molecular Mechanisms of Sister-Chromatid Exchange
Molecular Mechanisms of Sister-Chromatid Exchange
Mini review
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, United States
b Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551-0808, United States
Available online 6 December 2006
Abstract
Sister-chromatid exchange (SCE) is the process whereby, during DNA replication, two sister chromatids break and rejoin with
one another, physically exchanging regions of the parental strands in the duplicated chromosomes. This process is considered to be
conservative and error-free, since no information is generally altered during reciprocal interchange by homologous recombination.
Upon the advent of non-radiolabel detection methods for SCE, such events were used as genetic indicators for potential genotoxins/mutagens in laboratory toxicology tests, since, as we now know, most forms of DNA damage induce chromatid exchange upon
replication fork collapse. Much of our present understanding of the mechanisms of SCE stems from studies involving nonhuman
vertebrate cell lines that are defective in processes of DNA repair and/or recombination. In this article, we present a historical
perspective of studies spearheaded by Dr. Anthony V. Carrano and colleagues focusing on SCE as a genetic outcome, and the role
of the single-strand break DNA repair protein XRCC1 in suppressing SCE. A more general overview of the cellular processes and
key protein effectors that regulate the manifestation of SCE is also presented.
2006 Elsevier B.V. All rights reserved.
Keywords: Sister-chromatid exchange; Single-strand break DNA repair; CHO EM9; XRCC1; Bloom syndrome; Homologous recombination; DNA
replication forks
1. Introduction
0027-5107/$ see front matter 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.mrfmmm.2006.11.017
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Searching PubMed with Carrano AV, Tonys interest in the processes that affect chromosome stability
becomes obvious. His contributions to our understanding
of the mechanisms that are involved in or that police the
formation of genetic alterations are considerable. These
accomplishments include the development of assays to
measure chromosomal aberrations, the characterization
of genetic alterations associated with exposure to laboratory or environmental genotoxins, the delineation of
the contributions of specific DNA repair factors to the
maintenance of genome integrity, and the identification
of genetic mutations that lead to disease manifestation.
Indeed, Tonys enormous efforts in the Human Genome
Project allowed him to participate in defining several
genetic disorders associated with human disease.
1.3. Tony Carranos impact on DNA repair from the
perspective of Larry Thompson
I first met Tony one winter evening in 1973 at the
Holiday Inn in Livermore when I came for my interview
with Mort Mendelsohn, who was recruiting new staff
for the program he was reorganizing. Tony was in the
restaurant (or bar) with Mike Bender, who was puffing
on a cigar (I learned this year that Mike has also recently
passed away). We chatted awhile to see what we might
have in common. They were both cytogeneticists, and
Tony later went to work at LLNL.
After several years at LLNL, Tony and I developed a
very natural and productive scientific collaboration; with
our first publication in Nature in 1978, we were off to a
good start (see photograph of us in Fig. 2). This paper,
with Tony as the first author, was about chromosomal
SCE induced by chemical mutagens. Tony and I went on
to publish more than 20 papers together. As I isolated new
DNA repair mutants of hamster cells, which required
extensive characterization, Tony enthusiastically applied
his expertise in chromosome analysis to greatly enhance
the discoveries with these mutant cell lines. My last publication with Tony was in 1995 not long before he left
the Program.
Early on, Tony became my group leader, and this
arrangement was quite beneficial to both of us. As my lab
began isolating human DNA repair genes, Tonys DNA
sequencing shop run by Jane Lamerdin was invaluable
in determining the sequence of some of the first cloned
human repair genes. This was an exciting time for us
as we compared the sequences of the human genes with
those in other organisms such as yeast and mice, and
began to develop ideas about what the gene products
were doing at the molecular level. It was highly gratifying for me when the work Tony and I did together led to
D.M. Wilson III, L.H. Thompson / Mutation Research 616 (2007) 1123
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Fig. 1. (A) Mechanism for occurrence of SCE when the leading strand of a replication fork encounters a SSB or gap. Steps 1 and 2: fork approaches
a SSB. Step 3: fork breaks. Step 4: repair synthesis occurs at the gap in the unbroken chromatid. The curved black arrow signifies a conformational
change to facilitate visualization of subsequent events. Step 5: processing of the broken duplex creates a 3 single-strand tail. Step 6: Rad51 mediates
strand invasion. Step 7: resolution of the Holliday junction in the orientation shown by the green arrows results in SCE, as illustrated by the red/blue
color junctions in the new parental strands. Resolution in the orientation shown by the purple arrowheads would not produce an SCE. Step 8:
the replication fork is restored. (B) Extraordinarily high SCE in CHO EM9 metaphase stained with propidium iodide (red) and antibody against
BrdUrd-substituted single-stranded DNA (following denaturation). The cells were grown for one cycle in the presence of BrdUrd, followed by one
cycle in normal medium, and stained according to Ref. [5]. The arrow indicates the only chromosome not having at least one exchange event. (C)
Human hTERT-NHF1 fibroblast, after two cycles of growth in 25 M BrdUrd, stained for SCE using DAPI (which stains DNA; blue fluorescence)
and antibody against BrdUrd-substituted DNA (green fluorescence). Arrows mark sites of exchange.
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D.M. Wilson III, L.H. Thompson / Mutation Research 616 (2007) 1123
Fig. 3. (A) Linear diagram of XRCC1. XRCC1 N = N-terminal DNA binding and POL interaction domain; BRCT1 and BRCT2 = the central and
C-terminal BRCT (BRCA1 C-terminus) domains. Direct physical interactors of XRCC1 are denoted, as are the regions within XRCC1 that they
interact. Amino acid locations are indicated (from 1 to 633). NLS = location of several putative nuclear localization signals. PCNA = proliferating
cellular nuclear antigen; OGG1 = 8-oxoguanine DNA glycosylase. See text for additional details. (B) Role of XRCC1 in BER/SSBR. Major steps of
BER/SSBR are denoted 15 to the left. In brief, a DNA glycosylase (e.g. OGG1) excises a damaged base from DNA (gray square), leaving behind
an apurinic/apyrimidinic (AP) site. The AP site is then typically incised by an AP endonuclease, primarily APE1 in mammals. The termini of the
resulting strand break are processed (i.e. the 5 -deoxyribose phosphate is removed, gray circle), and DNA POL (primarily) fills the nucleotide
gap (gray line). Finally, the remaining nick is sealed by a DNA ligase, such as LIG3. SSBs are also products of certain multifunctional DNA
glycosylases or the action of reactive oxygen species, both of which can generate 3 -obstructive ends such as phosphate groups (black circle).
Through direct physical interactions: PARP-1 recruits XRCC1 to a SSB site; XRCC1 facilitates POL organization at the SSB; XRCC1 promotes
PNKP 3 -phosphatase activity; XRCC1 both stabilizes LIG3 protein levels and facilitates nick ligation.
D.M. Wilson III, L.H. Thompson / Mutation Research 616 (2007) 1123
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D.M. Wilson III, L.H. Thompson / Mutation Research 616 (2007) 1123
Table 1
Proteins that regulate spontaneous SCEa
Protein function
Effectors of SSBR
XRCC1
Stabilizes LIG3 protein, and acts as a non-enzymatic
assembly factor in BER/SSBR
PARP-1
Binds DNA break ends and coordinates a strand break
repair response
LIG3
Ligates DNA nicks
Effectors of HR
BLM
Rad51
Rad54
XRCC2
XRCC3
Rad51B
Rad51C
Rad51D
Dissociates D-loop recombination intermediates and promotes dissolution of double Holliday junctions
Mediates strand transfer in HR
Facilitates HR
Promotes Rad51 focus formation and HR
Promotes Rad51 focus formation and HR
Promotes Rad51 focus formation and HR
Promotes Rad51 focus formation and HR
Promotes Rad51 focus formation and HR
Effectors of TLS
Rad18
Cofactor of Rad6 (ubiquitin conjugating enzyme) in TLS
Revl
Deoxycytidyl transferase in TLS
Rev3
Polymerase catalytic subunit
Rev7
Polymerase regulatory subunit
rev1 rev3 rev 7 triple mutant
[5,15,117]
[16,17]
[83]
[42,118,119]
[29]
[29,32,119]
[121123]
[120,121]
[121]
[121,124,125]
[30,31,121]
[97,101]
[98,100]
[99,100]
[100]
[100]
Not listed are FANC genes, which seem to influence SCE in DT40 cells but not mammalian cells. The main categories for proteins modulating
SCE are indicated in bold. See text for more details. The arrows depict the increase (), decrease (), or no change () in spontaneous SCE level in
mutant cells. The size of each arrow represents the degree of change: small arrow, <two-fold; medium arrow, two- to five-fold; large arrow 10-fold.
Each arrow represents a separate study.
6. Future directions
It is evident from the above discussion that an
enhancement of SCE in repair-proficient cells can be
expected to occur as part of the response of cycling cells
to virtually any genotoxic agent [19,34,111]. Replication forks collapse when they encounter DNA blocking
lesions introduced by mutagens or upon drug inhibition of replication, especially at doses that produce cell
killing. Broken forks are subsequently subject to repair
mainly by HR, which results in increased SCE. Thus, by
extension, altered SCE levels will be a feature of most,
but clearly not all, cells defective in the repair of DNA
damage. We suggest that future studies more exhaustively evaluate this endpoint in available DNA repair
mutant cells, with and without exposure to exogenous
sources of DNA lesions. Mutants that do not show a
change in SCE frequency may reflect: (i) that the substrates of the missing protein do not influence exchange,
or (ii) there exists an altered bias in resolving Holliday
junctions, such as presumably in rad51d rodent cells
[30,31]. This latter issue deserves study, and may prove
insightful about the functions of the Rad51 paralogs.
D.M. Wilson III, L.H. Thompson / Mutation Research 616 (2007) 1123
Acknowledgements
We thank Drs. John Hinz (LLNL), Sudha Sharma
(NIA), and Jinshui Fan (NIA) for their insightful comments. We extend a special thanks to Dr. Paul Wilson
(LLNL) for providing the image in Fig. 1C, and J. Fan
for sharing his unpublished results. This research was
supported (in part) by the Intramural Research Program
of the NIH, National Institute on Aging. A portion of
this work (LHT) was performed under the auspices of
the U.S. Department of Energy by the University of California, Lawrence Livermore National Laboratory under
Contract No. W-7405-Eng-48 and funded by the DOE
Low-Dose Radiation Research Program and NCI/NIH
grant CA11256.
19
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