This
article discuss about problems with free DNA ends in eukaryotic cells. Free
reactive DNA ends are caused by double-strand DNA breaks (DSB) which results in
the development of various mechanisms to ensure that free DNA ends are
non-reactive. DSB is a chemically modified process and is considered very
toxemic to the cell and genetic materials. It can generate free ends DNA that
has to be repaired. Free end DNA can be very dangerous to the eukaryotic
organism. Recombination-base mechanism is a mechanism that generates region of
homology pairs during meiosis and mitosis. This may result in translocation and
deletion of DNA and could lead genome instability when DNA fails to repair
itself, or several x-linked disease such as the Turner's syndrome that is related
to the non-allelic homologous combination and random arrangement of the
X-chromosome from female. Free end DNA relates to x-linked diseases because DNA
is engaged in the homologous recombinant with X chromosome in female during
meiosis. This provides more possibility for mispairing recombination.
http://www.hindawi.com/isrn/molecular.biology/2012/345805/fig1/ (image: Structure of DSB)
http://atlasgeneticsoncology.org/Deep/Images/DoubleStrandBreak4.jpg
The
double-stand DNA breaks (DSB) occur during the process of DNA replication when
the phosphodiester backbone of both strands of the same DNA helix is broken and
is separated. Though DSB may lead to genetic diseases because it is the cause
of alteration of the DNA structure and generate free DNA ends, its occurrence
is required throughout the cell cycle. Free DNA ends are "unprotected
DNA" that should remain inactive. If the fragment is reactive, it will intact
with other DNA ends. This is call the genomic fusion, which could lead to
genomic instability from the breakdown of one eukaryotic chromosome to long
term effects such as inherited diseases or somatic origin diseases such as
cancer or syndromes. The risk for genomic instability, thus, can be trigger
from recombinant mechanisms. Therefore it is difficult to cease the unprotected
DNA from activating or keep free-ends non-reactive because scientists cannot
control the repairing process of DNA free end and the presence of DSB is
required in the cell cycle.
http://www.genome.jp/kegg/pathway/ko/ko03450.png
The
article also talks about factors that may increase or lower the rate of
occurrence of DSB. Ionizing radiation and radiomimetic chemicals such
short-wavelength UV are chemical factors that increase the rate of occurrence
of DSB. Meiotic and mitotic recombination is the only mechanisms that can
generate genetic diversity and requires DSB. Recombination of non-sister
chromatids in prophase I of meiosis create a largest variability of unique
allelic combination. Both chromosomes in meiosis are allelic homologous despite
the DNA sequence. Non-allelic homologous combination (NAHR), in the other hand
is a recombination between chromosomes that share the same region but at a
different locus. It happens between DNA sequences where there is an excess
amount of high sequence homology pairs. This occurs less frequent, though it is
responsible as a cause for inherited diseases and cancer. Both types for
recombination, allelic and non-allelic may cause rearrangement of genome
fragments. From exchanging genetic materials of sister chromatids during
mitosis or meiosis allow genetic variability, however excess sister chromatid
exchange can defect in the DNA regarding the production of proteins, leading to
diseases such the Turner's syndrome.
Turner
syndrome is one possible result of DSB and DNA recombination. The Turner
syndrome, or 45(XO) is a phenotype of females that have monosomy X. This means
that they only have one X-chromosome instead of two in their genome (45 chromosomes
in total). Individuals with Turner’s syndrome are usually short, have broad
chest, low-set ears and does not menstruate. It has been found that there is a
cluster of inverts repeated sequences in the X chromosome, which is a result
from rearrangement from non-allelic homologous recombination.
To
conclude, the double-strand DNA breaks (DSB) is considered a dangerous process
of the DNA replication because one prime side (either 3' or 5') is left free
and unprotected. If free-ended DNA is activating, it will interact and intact
with other DNA ends. This will result in the genomic fusion and may lead to
serious consequences such inherited (syndrome) or somatic origin diseases
(cancer). Therefore, DNA repair mechanism is required to repair DNA ends. It's
goal is to maintain the balance of genome stability and genome variability to
cease possible mutations of the cell. However, DNA repair mechanism can be
harmful as well since there are various types of mechanisms (i.e. recombinant
vs. non recombinant) which could lead to unique combination of both somatic and
sex cell, and result in inherited and/or somatic diseases as well.
Word Count: 740
for Double-Strand Break Repair in Mammalian
Cells." SRN Molecular Biology.
Volume 2012
Article ID 345805.16 pages (2012): 1-16. Web. 25
Oct. 2013.
<http://www.hindawi.com/isrn/molecular.biology/2012/345805/>.
joining DNA double-strand break repair pathway
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25 Oct. 2013. <http://www.ncbi.nlm.nih.gov/pubmed/16822175>.
<http://www.genome.jp/dbget-bin/www_bget?
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