Which Three Processes Are Methods of Genetic Recombination

Which Three Processes Are Methods of Genetic Recombination

How does Deoxyribonucleic acid recombination work? It occurs oftentimes in many unlike cell types, and it has of import implications for genomic integrity, evolution, and human illness.

© 2008 Nature Education Adjusted from Sharp, L. (1934) Introduction to Cytology (McGraw–Hill, New York), pp. 303, 330, 333 (2008). All rights reserved.

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DNA
recombination
involves the exchange of genetic material either between multiple chromosomes or between unlike regions of the aforementioned chromosome. This process is generally mediated by
homology; that is,
homologous
regions of chromosomes
line
up in training for exchange, and some degree of sequence identity is required. Various cases of nonhomologous recombination do exist, however.

1 important example of recombination in
diploid
eukaryotic
organisms is the exchange of genetic information betwixt newly duplicated chromosomes during the process of
meiosis. In this instance, the issue of recombination is to ensure that each
gamete
includes both maternally and paternally derived genetic information, such that the resulting
offspring
will
inherit
genes
from all four of its grandparents, thereby acquiring a maximum amount of genetic diversity. Recombination is also used in
Dna repair
(particularly in the repair of double-stranded breaks), as well as during Deoxyribonucleic acid
replication
to aid in filling gaps and preventing stalling of the
replication fork. In these cases, a sister
chromatid
serves as the donor of missing fabric via recombination followed past DNA synthesis.

The part of recombination during the inheritance of chromosomes was first demonstrated through experiments with maize. Specifically, in 1931, Barbara McClintock and Harriet Creighton obtained bear witness for recombination by physically tracking an unusual knob structure inside certain maize chromosomes through multiple genetic crosses. Using a
strain
of maize in which one fellow member of a chromosome pair exhibited the knob but its homologue did not, the scientists were able to testify that some
alleles
were physically linked to the knobbed chromosome, while other alleles were tied to the normal chromosome. McClintock and Creighton and so followed these alleles through meiosis, showing that alleles for specific phenotypic traits were physically exchanged between chromosomes. Evidence for this finding came from the fact that alleles commencement introduced into the cross on a knobbed chromosome later appeared in offspring without the knob; similarly, alleles initially introduced on a knobless chromosome later appeared in
progeny
with the knob (Figure 1).

Recombination too occurs in prokaryotic cells, and information technology has been especially well characterized in
E. coli. Although
bacteria
do non undergo meiosis, they do engage in a type of sexual
reproduction
called
conjugation, during which genetic material is transferred from one bacterium to some other and may be recombined in the recipient
cell. Every bit in eukaryotes, recombination likewise plays important roles in Dna repair and replication in prokaryotic organisms.

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Models of Recombination

Panel A is an electron micrograph showing a Holliday junction. Panel B shows two diagrams of possible Holliday junction configurations.

A) © 1979 Cold Jump Harbor Laboratory. Potter, H. & Dressler, D. DNA recombination:
in vivo
and
in vitro
studies.
Common cold Spring Harb. Symp. Quant. Biol.
43, 969–985 (1979). All rights reserved. B) © 2004 Nature Publishing Group. Liu, Y.
et al. Happy Hollidays: 40th ceremony of the Holliday junction.
Nature Reviews Molecular Prison cell Biology
5, 940 (2004). All rights reserved.

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Although mutual, genetic recombination is a highly circuitous process. It involves the alignment of two
homologous DNA
strands (the requirement for homology suggests that this occurs through
complementary
base-pairing, simply this has non been definitively shown), precise breakage of each strand, exchange betwixt the strands, and sealing of the resulting recombined molecules. This process occurs with a high degree of accuracy at high
frequency
in both eukaryotic and prokaryotic cells.

The basic steps of recombination can occur in two pathways, according to whether the initial intermission is single or double stranded. In the single-stranded
model, following the alignment of homologous chromosomes, a break is introduced into one DNA strand on each chromosome, leaving ii complimentary ends. Each end then crosses over and invades the other chromosome, forming a structure called a
Holliday junction
(Figure 2). The next step, chosen
branch
migration, takes identify equally the junction travels downward the DNA. The junction is then resolved either horizontally, which produces no recombination, or vertically, which results in an exchange of Dna.

In the alternating pathway initiated past double-stranded breaks, the ends at the breakpoints are converted into unmarried strands by the addition of 3′ tails. These ends can and so perform strand invasion, producing two Holliday junctions. From that signal forward, resolution proceeds equally in the unmarried-stranded model (Figure 3). (Notation that a 3rd model of recombination, synthesis-dependent strand annealing [SDSA], has besides been proposed to business relationship for the lack of crossover typical of recombination in mitotic cells and observed in some meiotic cells to a lesser degree.)

Recombination Enzymes

This diagram shows how double-strand breaks in DNA can be repaired by either the double-strand break repair pathway or the synthesis-dependent strand annealing pathway. The end resection, strand invasion, and DNA synthesis processes that occur in both pathways are outlined in panel A. Double-stranded DNA is depicted as two blue, horizontal parallel lines. The double-strand break (DSB) appears as a gap of empty space that interrupts the two strands. A homologous DNA strand is shown in red with no gap or break. During end resection, the 3-prime end of the top strand in the left piece of broken DNA and the 3-prime end of the bottom strand in the right piece of broken DNA is removed. The remaining DNA strand hybridizes to the homologous DNA strand to begin new DNA synthesis. New DNA synthesis is represented by a dashed line with an arrow indicating the direction of synthesis. The double-strand break repair pathway is shown in panel B: both broken strands are resynthesized using the homologous DNA strand as a template. The synthesis-dependent strand annealing pathway is shown in panel C: only one broken strand is resynthesized using the homologous DNA strand as a template, and the second broken strand is then synthesized based on the newly repaired DNA strand.

© 2006 Nature Publishing Group Sung, P.
et al.
Mechanism of homologous recombination: mediators and helicases take on regulatory functions.
Nature Reviews Molecular Cell Biology
7,
741 (2006). All rights reserved.

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No thing which pathway is used, a number of enzymes are required to consummate the steps of recombination. The genes that lawmaking for these enzymes were start identified in
Eastward. coli
past the isolation of
mutant
cells that were deficient in recombination. This research revealed that the
recA
gene
encodes a
protein
necessary for strand invasion. Meanwhile, the
recB,
recC, and
recD
genes code for three polypeptides that join together to course a protein complex known as RecBCD; this complex has the capacity to unwind double-stranded DNA and cleave strands. Two other genes,
ruvA
and
ruvB, encode enzymes that catalyze
branch migration, while Holliday structures are resolved past the protein
resolvase, which is production of the
ruvC
gene. Several enzymes involved in DNA replication, such as ligase and
DNA polymerase, likewise contribute to recombination (Clark, 1973).

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In eukaryotes, recombination has been perhaps most thoroughly studied in the budding
yeast
Saccharomyces
cerevisiae. Many of the enzymes identified in this yeast have as well been found in other organisms, including mammalian cells. Such studies reveal that the
Rad
genes (named for the fact that their activity was institute to be sensitive to
radiation) play a key role in eukaryotic recombination. In item, the
Rad51
gene, which is homologous to
recA, encodes a protein (called Rad51) that has recombinase activity. This gene is highly conserved, simply the accessory proteins that assist Rad51 announced to vary among organisms. For example, the Rad52
poly peptide
is found in both yeast and humans, simply it is missing in

Drosophila melanogaster

and
C. elegans.

In eukaryotic cells, single-stranded Deoxyribonucleic acid (ssDNA) becomes chop-chop coated with the protein RPA (replication protein A). RPA has a higher affinity for ssDNA than Rad51, and information technology therefore can inhibit recombination by blocking Rad51’s access to the unmarried strand needed for invasion. In yeast, however, bounden of Rad51 to ssDNA is enhanced by the proteins Rad52 and the complex Rad55-Rad57. Once access has been gained, Rad51 polymerizes on the DNA strand to form what is chosen a presynaptic filament, which is a right-handed helical filament containing six Rad51 molecules and 18 nucleotides per helical repeat. The search for Deoxyribonucleic acid homology and formation of the junction between homologous regions is then carried out within the catalytic eye of the filament.

In addition to proteins that assist Rad51 activity, there are besides some proteins that inhibit it. In yeast, for instance, the
helicase
Srs2 dismantles the Rad51-ssDNA complex, while the proteins Sgs1 and BLM inhibit the complex. It is thought that these proteins play a part in preventing recombination during DNA replication when it is non needed.

In humans, the
tumor suppressor
genes
BRCA1
and
BRCA2
besides play a office in regulating recombination. Individuals who are
heterozygous
for
BRCA2
are subject to increased
run a risk
for chest and ovarian
cancer; loss of both alleles causes Fanconi’s anemia, a genetic
disease
characterized past predisposition to cancer, among other defects.
BRCA2
appears to promote
Rad51
binding to ssDNA (Li & Heyer, 2008; Modesti & Kanaar, 2001).

How Are Homologous Sequences Brought Together?

As previously described, the enzymes and mechanisms that acquit out the process of
homologous recombination
are adequately well delineated. Not then well understood is the important question of how homologous sequences come to be in proximity so that recombination can proceed. In their 2008 review, Barzel and Kupiec describe two alternate hypotheses, one of which they call the
null model. This model proposes that homologues find one another through a passive process of diffusion, in which the DNA sequence at the cleaved finish of a strand is sequentially compared to all of the other potential end sequences in the
genome. In club for improvidence to account for the rapid repair of double-stranded breaks observed in yeast, however, Barzel and Kupiec summate that each homology search would accept to proceed at a speed 40 times faster than the rate at which DNA polymerase adds a single
nucleotide
to a replicating Dna chain, which seems unlikely (Barzel & Kupiec, 2008).

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An alternate hypothesis proposes that homologous chromosomes reside in pairs constitutively. Acting against this hypothesis is the finding that in induced recombination experiments, the cleaved ends of strands recombine with what are chosen ectopic homologues (areas of fortuitous sequence identity) as frequently as they recombine with their true homologous chromosomes. Furthermore, although homologous pairing has been observed in somatic cells of some organisms (e.g.,
Drosophila,
Neurospora), it is non widely seen in the cells of other organisms, including mammals. As Barzel and Kupiec (2008) betoken out, the absenteeism of general homologous pairing does not necessarily mean random assortment. Instead, discrete sections of chromosomes may be required for homology. The employ of subdomains for homology searches would reduce the time it takes to find a homologous partner. Despite such theories, the exact mechanism responsible for locating and lining upward homologous segments remains to be adamant.

References and Recommended Reading


Barzel, A., & Kupiec, M. Finding a match: How do homologous sequences get together for recombination?
Nature Reviews Genetics
nine, 27–37 (2008) doi:10.1038/nrg2224 (link to article)

Clark, A. J. 1973. Recombination deficient mutants of
Eastward
. coli
and other bacteria.
Annual Review of Genetics
7, 67–86 (1973) doi:10.1146/annurev.ge.07.120173.000435

Li, Ten., & Heyer, W. D. Homologous recombination in Dna repair and DNA damage tolerance.
Cell Research
18, 99–113 (2008)

Liu, Y., & West, South. C. Happy Hollidays: Fortieth anniversary of the Holliday junction.
Nature Reviews Molecular Cell Biology
5, 937–944 (2004) doi:10.1038/nrm1502 (link to commodity)

Modesti, K., & Kanaar, R. Homologous recombination: From model organism to man disease.
Genome Biology
2, 1014.1–1014.5 (2001)

Sung, P., & Klein, H. Mechanism of homologous recombination: Mediators and helicases take on regulatory functions.
Nature Reviews Molecular Prison cell Biology
vii, 739–750 (2006) doi:10.1038/nrm2008 (link to article)

Which Three Processes Are Methods of Genetic Recombination

Source: http://www.nature.com/scitable/topicpage/genetic-recombination-514