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Chromosomal translocation
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==DNA double-strand breaks with translocations== The initiating event in the formation of a translocation is generally a [[DNA damage (naturally occurring)|double-strand break in chromosomal DNA]].<ref name="Agarwal2006">{{cite journal |last1=Agarwal |first1=S. |last2=Tafel |first2=A. A. |last3=Kanaar |first3=R. |date=2006 |title=DNA double-strand break repair and chromosome translocations |journal=DNA Repair |volume=5 |issue=9β10 |pages=1075β1081 |doi=10.1016/j.dnarep.2006.05.029 |pmid=16798112}}</ref> Double stranded breaks in chromosomal DNA can occur for many reasons, however a major role in generating these translocations is the [[non-homologous end joining]] (NHEJ) pathway.<ref name="Agarwal2006" /><ref>{{cite book |doi=10.1007/978-3-319-20291-4_1 |chapter=DNA Repair and Chromosomal Translocations |title=Chromosomal Instability in Cancer Cells |series=Recent Results in Cancer Research |date=2015 |last1=Bohlander |first1=Stefan K. |last2=Kakadia |first2=Purvi M. |volume=200 |pages=1β37 |isbn=978-3-319-20290-7 }}</ref> When this pathway functions appropriately, it restores a DNA double-strand break by reconnecting the originally broken ends using their sticky or blunt ends that have been generated by the enzyme and protein machinery. However, when the NHEJ pathway acts inappropriately, it may join ends incorrectly, therefore resulting in genomic rearrangements including translocations. These incorrect combinations are the result of sequences in close proximity that have similar homology, but not perfect homology, yet it is recognized by the repair machinery as perfect. This then leads the machinery to begin repairing using NHEJ with the wrong sequences, resulting in deletions and insertions of specific nucleotides, or the joining of incorrect end sequences.<ref>{{cite journal |last1=Steyer |first1=Benjamin |last2=Cory |first2=Evan |last3=Saha |first3=Krishanu |title=Developing precision medicine using scarless genome editing of human pluripotent stem cells |journal=Drug Discovery Today: Technologies |date=August 2018 |volume=28 |pages=3β12 |doi=10.1016/j.ddtec.2018.02.001 |pmid=30205878 |pmc=6136251 |quote=Non-homologous end joining (NHEJ)βan error prone DNA repair process where double strand breaks are directly ligated, commonly resulting in insertion or deletion mutations. }}</ref> Ultimately, these issues arise due to a misread of the homologous sequences by the protein or enzyme machinery, and leads to the mis-incorporation of incorrect sequences into the genome. when the genomes of slightly homologous sequences are in too close of proximity, resulting in the machinery becoming confused or mistaking the wrong sequence for the correct one.<ref>{{cite journal |last1=Rocha |first1=P. P. |last2=Chaumeil |first2=J. |last3=Skok |first3=J. A. |date=2013 |title=Molecular biology. Finding the right partner in a 3D genome |journal=Science |volume=342 |issue=6164 |pages=1333β1334 |doi=10.1126/science.1246106 |pmc=3961821 |pmid=24337287}}</ref> Another influence in generating DNA double stranded break translocations is through the creation of AID translocations. These sequences are the result of a deamination procedure of a cytosine nucleotide into a uracil nucleotide. This change ultimately results in a mismatch between the complementary sequence and its target sequence, therefore resulting in a translocation. When further processed by specific endonucleases, this uracil leads to a mutation or a double stranded break.<ref>{{Cite journal |last1=Nambiar |first1=Mridula |last2=Raghavan |first2=Sathees C. |date=August 2011 |title=How does DNA break during chromosomal translocations? |journal=Nucleic Acids Research |volume=39 |issue=14 |pages=5813β5825 |doi=10.1093/nar/gkr223 |issn=1362-4962 |pmc=3152359 |pmid=21498543}}</ref> Once again, these double stranded break and the mismatch that occurred lead to a translocation of the genomic sequence, which in turn have effect on the chromosome the DNA is present on. Finally, new information is surfacing regarding the influence of exogenous rare-cutting endonucleases on DNA double stranded breaks and their resulting chromosomal translocations.<ref>{{cite journal |last1=Jasin |first1=Maria |title=Genetic manipulation of genomes with rare-cutting endonucleases |journal=Trends in Genetics |date=June 1996 |volume=12 |issue=6 |pages=224β228 |doi=10.1016/0168-9525(96)10019-6 |pmid=8928227 |doi-access=free }}</ref><ref name=":17">{{cite journal |last1=Povirk |first1=Lawrence F. |title=Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks |journal=DNA Repair |date=September 2006 |volume=5 |issue=9β10 |pages=1199β1212 |doi=10.1016/j.dnarep.2006.05.016 |pmid=16822725 }}</ref> Specifically, during DNA double strand break repair, reflections of misjoining of exchanged sequence ends have be noted, primarily due to the mishomology present by the NHEJ pathway. However, at these specific break points, additional nucleic acid and DNA sequence loss has been found, therefore leading to the conclusion that additional exogenous rare-cutting endonucleases are present at various locations on these strands. Each deletion results in a varying size, location or cut version, ultimately suggesting DNA degradation by endonucleases prior to NHEJ joining.<ref name=":17" /> Additional influences on DNA degradation similar to that of exogenous rare-cutting endonucleases has also been noted as a result of cytotoxic chemotherapy,<ref>{{Cite web |title=Chemotherapy - What it is, types, treatment and side effects |url=https://www.macmillan.org.uk/cancer-information-and-support/treatment/types-of-treatment/chemotherapy#:~:text=we%20can%20help-,What%20is%20chemotherapy?,are%20carried%20in%20the%20blood. |access-date=2025-04-11 |website=www.macmillan.org.uk |language=en}}</ref> [[ionizing radiation]], although further research is needed in order to provide more conclusive and viable answers.<ref name=":18">{{Cite journal |last1=Qiu |first1=Zhijun |last2=Zhang |first2=Zhenhua |last3=Roschke |first3=Anna |last4=Varga |first4=Tamas |last5=Aplan |first5=Peter D. |date=2017-02-22 |title=Generation of Gross Chromosomal Rearrangements by a Single Engineered DNA Double Strand Break |journal=Scientific Reports |language=en |volume=7 |issue=1 |pages=43156 |bibcode=2017NatSR...743156Q |doi=10.1038/srep43156 |pmid=28225067 |pmc=5320478 |issn=2045-2322|hdl=2437/288170 |hdl-access=free }}</ref> Overall, through various mechanisms, DNA double-strand breaks and sources of DNA double-strand break repair are able to generate both reciprocal and non reciprocal chromosomal translocations.<ref name=":17"/> Such DNA breaks and repair mechanisms are also able to generate gross chromosomal mutations, inclusive of not only translocations, but also inversions, amplifications and simple deletions, all resulting in null or dangerous transformations.<ref name=":18" />
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