Biology Reference
In-Depth Information
and chromatin structure are disrupted in human cancers, implying that altered
chromatin structure in tumor cells may impact DSB repair, increasing genomic
instability and contributing to the progression of cancer.
I. The DNA Damage Response
Mammalian cells are constantly exposed to genotoxic events which can
directly damage the DNA in the cell. Endogenous DNA damage can occur
through the production of oxygen radicals during aerobic respiration or
through errors created during DNA replication. However, a significant source
of DNA damage is exposure to exogenous DNA-damaging agents. For exam-
ple, aflatoxins, heavy metals, cigarette smoke, radiation (e.g. UV exposure) and
many environmental and man-made chemicals can modify or cross-link bases
on the DNA double helix. Consequently, cells must continuously monitor the
integrity of the DNA and rapidly remove these lesions. The failure to correctly
maintain genome integrity can lead to the generation of mutations and de-
letions, constituting the underlying mechanism of carcinogenesis.
To maintain genome integrity, cells have multiple DNA repair pathways
that are designed to detect and remove specific lesions. These include mis-
match repair (removal of mismatched bases), base excision repair (removal
of simple DNA adducts), nucleotide excision repair (bulky lesions and UV
damage), the Fanconi anemia pathway (interstrand cross-links), and DNA
double-strand break (DSB) repair (caused by ionizing radiation (IR)
or replication fork collapse) (reviewed in Ref.
1
). Collectively, these pathways
are referred to as the DNA damage response (DDR). Although these diverse
DNA repair pathways focus on distinct lesions, there is considerable functional
overlap between the individual proteins so that many DDR proteins function
in multiple DNA repair pathways. There is, therefore, significant cross talk
between DDR proteins during DNA repair.
In this review, we focus on the repair of DNA DSBs. DSBs can occur in
cells through several mechanisms. For example, stalling of replication forks due
to DNA damage can lead to fork collapse, creating DSBs that must be repaired
before replication can continue. In addition, exposure of cells to IR generates
large numbers of DNA strand breaks, including DSBs. IR is widely used to
treat cancer, and derives its therapeutic effect by generating DSBs within the
tumor mass, thereby preferentially killing the rapidly dividing tumor cells.
However, tumor responsiveness to IR is variable, and there is considerable
urgency to understand the molecular pathway by which cells detect and repair
DSBs, with the aim of identifying differences between normal and tumor cells
that can be exploited to improve the therapeutic index of radiation therapy. In
