Biology Reference
In-Depth Information
Homologous recombination (HR) is a mechanistically conserved pathway
that ensures maintenance of genomic integrity. During meiosis, HR results in
DNA crossover events between homologous chromosomes that produce the
genetic diversity inherent in germ cells. The physical connection established
between homologs during the crossover event is essential to facilitate correct
chromosome segregation. HR is also involved in maintenance of somatic cell
genomic stability by restoring replication after a stalled replication fork has
encountered a DNA lesion or strand break, as well as following exogenous
stresses such as ionizing radiation that induce DNA double-strand breaks. The
importance of HR can be gauged by the conservation of HR genes and
functions from bacteria to man. Here we review the players and mechanics
of eukaryotic HR.
DNA double-stranded breaks (DSBs) are generated spontaneously by
radiation and chemical damage as well as intentionally as part of the
chromosome-pairing process during meiosis. Genome instability resulting from
DSB recombination repair (RR) defects has been linked to a variety of human
cancers including hereditary breast cancer (BRCA1/2) as well as hematopoietic
and other solid tumors (ataxia telangiectasia mutated (ATM), Nijmegen breakage
syndrome (NBS), Fanconi anemia (FANC), and Bloom's syndrome (BLM))
among others.
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Unlike many repair pathways, RR engenders a complex cas-
cade of responses that include cellular signaling integrated with the physical
processes of DSB repair.
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The DSB repair reaction itself involves a complex
cascade of enzymatic reactions that must manage the chromatin composite on
the broken donor DNA in order to search and pair with the assembled chromatin
of a homologous acceptor DNA. Deficiencies in any one of the multitudes of
steps will affect the outcome of the RR process and ultimately affect genome
stability. Understanding of the biophysical events associated with the DSB repair
reaction, which rely on targeting redundant or overlapping repair pathways that
ultimately result in a synergistic therapeutic response in cancer patients, is
important as combinatorial chemical strategies are under development.
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I. Meiosis
All sexually reproducing organisms undergo meiosis—a process that re-
duces the cellular diploid content to produce haploid gametes. RR has been
coopted and is essential for the completion of meiosis. Meiosis begins with
replication that forms sister chromosomes (chromatids) and is followed by a
pairing process
spatially associates chromosome homologs.
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