|
DNA
double-strand breaks (DSBs) are the most deleterious type
of DNA damage. Failure in repair of DSBs may lead to chromosomal
translocation and interstitial deletion, culminating in genomic
instability and cancer. DSBs are generally repaired by two
main pathways - Homologous Recombination (HR) and Nonhomologous
DNA End Joining (NHEJ). HR predominantly occurs in lower organisms,
requires extensive homology and is error-free. By contrast,
NHEJ is the more common repair pathway in higher organisms
such as humans and other mammals. NHEJ involves modification
of the ends followed by joining using very little/no homology.
In this review, the authors discuss the mechanism of HR and
NHEJ-mediated joining of DSBs.
DNA
in the living cells is continuously subjected to many chemical
alterations. Failure in repair of DNA damages may cause chromosomal
instability leading to oncogenesis, apoptosis or severe failure
of cell functions (Kirsch, 1993; and Raghavan and Lieber,
2006). In order to protect the genomic integrity and stability,
the genetic information encoded in the DNA has to remain uncorrupted
and any alteration in the DNA must be corrected.
Various
exogenous and endogenous agents that produce damage in the
DNA include ionizing radiation such as gamma rays and x-rays,
highly reactive oxygen radicals, ultraviolet rays, radiomimetic
chemicals, physiological process and replication across a
nick. Single-strand breaks, double-strand breaks (DSBs), pyrimidine
dimers, mismatched bases, modified bases are examples of the
most common damages in the DNA. Cells are equipped with various
DNA repair pathways to counteract DNA damages generated both
spontaneously and as a result of exposure to exogenous DNA
damaging agents. Normally damages due to alterations in the
bases are repaired by excision repair which include nucleotide
excision repair (removes UV-induced pyrimidine dimers), base
excision repair (removes modified bases from the DNA), and
mismatch repair (removes mismatches generated during DNA replication)
or DNA double-strand break repair (reviewed by Kirsch, 1993;
Friedberg, 2003; Wyman et al., 2004; and Hefferan and
Tomkinson, 2005).
Among
the different DNA damages, DSBs are considered the most dangerous
DNA lesions. It is typically induced by intrinsic sources
such as the by-products of cellular metabolism (free radicals),
or introduced during normal physiological process such as
V(D)J joining of immunoglobulin genes or may be due to errors
in DNA replication or due to replication across the nick.
Extrinsic sources that induce DSBs include X-rays or g-rays.
These types of DNA damages are particularly detrimental because
both strands of DNA are damaged. Defects in the DSB repair
cause the accumulation of genomic rearrangements that promote
tumorigenesis (reviewed by Lieber et al., 2003 and
2006).
|
