Cancer develops when cells no longer follow their normal pattern
of controlled growth. In the absence or disregard of such
regulation, resulting from changes in their genetic makeup, these
errant cells acquire a growth advantage, expanding into
precancerous clones. Over the last decade, many studies have
revealed the relevance of genomic mutation in this process, be it
by misreplication, environmental damage, or a deficiency in
repairing endogenous and exogenous damage. Here, we discuss
homologous recombination as another mechanism that can result in
a loss of heterozygosity or genetic rearrangements. Some of these
genetic alterations may play a primary role in carcinogenesis, but
they are more likely to be involved in secondary and subsequent
steps of carcinogenesis by which recessive oncogenic mutations are
revealed. Patients, whose cells display an increased frequency of
recombination, also have an elevated frequency of cancer, further
supporting the link between recombination and carcinogenesis.

Alexander J. R. Bishop

Robert H. Schiestl

Homologous Recombination and Its Role in Carcinogenesis

XRCC2 protein shares weak amino acid sequence similarity with
Rad51, which is a central player in homologous recombinational
repair (HRR). Rad51 proteins assemble at the sites of HRR and form
visible nuclear foci in response to DNA damage. Xrcc2
hamster mutant irs1 cells are incapable of forming Rad51 foci
after ionizing irradiation or DNA cross-linking agent mitomycin C
treatment, though the Rad51 protein level is normal in the
mutant. The defect can be corrected in an XRCC2
transformant. Time course study showed that the irs1 cells
primarily lacked the early response (2 hours after
irradiation) to form small Rad51 foci (type 1) and later response
(8 hours after irradiation) to form large foci (type 2).
These results suggested that XRCC2 is essential for the assembly
of the DNA damage-induced Rad51 foci and that XRCC2 may play an
important role in the early stage of HRR.

Nan Liu

XRCC2 is Required for the Formation of Rad51 Foci Induced by Ionizing Radiation and DNA Cross-Linking Agent Mitomycin C

A major goal of current cancer research is to understand the
functional consequences of mutations in recombinational DNA
repair genes. The introduction of artificial recombination
substrates into living cells has evolved into a powerful tool to
perform functional analysis of DNA double strand break (DSB)
repair. Here, we review the principles and practice of current
plasmid assays with regard to the two major DSB repair pathways,
homologous recombination and nonhomologous end-joining. A
spectrum of assay types is available to assess repair in a wide
variety of cell lines. However, several technical challenges
still need to be overcome. Understanding the alterations of DSB
repair in cancers will ultimately provide a rational basis for
drug design that may selectively sensitize tumor cells to
ionizing radiation and chemotherapy, thereby achieving
therapeutic gain.

Henning Willers

Fen Xia

Simon N. Powell

Recombinational DNA Repair in Cancer and Normal Cells: The Challenge of Functional Analysis

Cellular processes such as transcription and DNA repair may be
regulated through diverse mechanisms, including RNA synthesis,
protein synthesis, posttranslational modification and protein
degradation. The 26S proteasome, which is responsible for
degrading a broad spectrum of proteins, has been shown to
interact with several nucleotide excision repair proteins,
including xeroderma pigmentosum B protein (XPB), Rad4, and Rad23.
Rad4 and Rad23 form a complex that binds preferentially to
UV-damaged DNA. The 26S proteasome may regulate repair by
degrading DNA repair proteins after repair is completed or,
alternatively, the proteasome may act as a molecular chaperone to
promote disassembly of the repair complex. In either case, the
interaction between the proteasome and nucleotide excision repair
depends on proteins like Rad23 that bind ubiquitin-conjugated
proteins and the proteasome. While the iteration between Rad4 and
Rad23 is well established, it will be interesting to determine
what other proteins are regulated in a Rad23-dependent manner.

K. Sweder

K. Madura

Regulation of repair by the 26S proteasome

Nucleotide excision repair (NER) is one of several DNA repair
pathways that are universal throughout phylogeny. NER has a broad
substrate specificity and is capable of removing several classes
of lesions to the DNA, including those that accumulate upon
exposure to UV radiation. The loss of this activity in
NER-defective mutants gives rise to characteristic sensitivities
to UV that, in humans, is manifested as a greatly elevated
sensitivity to exposure to the sun. Xeroderma pigmentosum (XP),
Cockayne’s syndrome (CS), and trichothiodystrophy (TTD) are
three, rare, recessively inherited human diseases that are linked
to these defects. Interestingly, some of the symptoms in
afflicted individuals appear to be due to defects in
transcription, the result of the dual functionality of several
components of the NER apparatus as parts of transcription factor
IIH (TFIIH). Studies with several model systems have revealed
that the genetic and biochemical features of NER are
extraordinarily conserved in eukaryotes. One system that has been
studied very closely is the budding yeast Saccharomyces
cerevisiae. While many yeast NER mutants display the expected
increases in UV sensitivity and defective transcription, other
interesting phenotypes have also been observed. Elevated mutation
and recombination rates, as well as increased frequencies of
genome rearrangement by retrotransposon movement and
recombination between short genomic sequences have been
documented. The potential relevance of these novel phenotypes to
disease in humans is discussed.

David J. Garfinkel

Adam M. Bailis

Nucleotide Excision Repair, Genome Stability, and Human Disease: New Insight from Model Systems

Ku proteins are associated with a variety of cellular processes
such as repair of DNA-double-strand breaks, telomere maintenance
and retrotransposition. In recent years, we have learned a lot
about their cellular and molecular functions and it has turned
out that Ku-dependent processes affect the stability of the
genome, both positively and negatively, in several ways. This
article gives an overview on the role of Ku in determining the
shape of the genome.

Anna A. Friedl

Ku and the Stability of the Genome

Lisa Wiesmüller

James M. Ford

DNA Damage, Repair, and Diseases

Werner syndrome is a premature aging disease caused by the
mutation in the WRN gene. The cloning and
characterization of the WRN gene and its product allows
investigators to study the disease and the human aging process at
molecular level. This review summarizes the recent progresses on
various aspects of the WRN research including functional
analysis of the protein, interactive cloning, complexes
formation, mouse models, and SNPs (single nucleotide
polymorphisms). These in depth investigations have greatly
advanced our understanding of the disease and elucidated future
research direction for Werner syndrome and the human aging
process.

Lishan  Chen

Junko  Oshima

Werner Syndrome

DNA damage incurred during the process of
chromosomal replication has a particularly high possibility of
resulting in mutagenesis or lethality for the cell. The SOS
response of Escherichia coli appears to be well adapted
for this particular situation and involves the coordinated
up-regulation of genes whose products center upon the tasks of
maintaining the integrity of the replication fork when it
encounters DNA damage, delaying the replication process (a DNA
damage checkpoint), repairing the DNA lesions or allowing
replication to occur over these DNA lesions, and then restoring
processive replication before the SOS response itself is
turned off. Recent advances in the fields of genomics and
biochemistry has given a much more comprehensive picture of the
timing and coordination of events which allow cells to deal with
potentially lethal or mutagenic DNA lesions at the time of
chromosomal replication.

David J. Crowley

Justin Courcelle

Answering the Call: Coping with DNA Damage at the Most Inopportune Time

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Papers are published upon acceptance, regardless of the Special Issue publication date.

BioMed Research International

DNA Damage, Repair, and Diseases

DNA Damage, Repair, and Diseases

Articles

Homologous Recombination and Its Role in Carcinogenesis

XRCC2 is Required for the Formation of Rad51 Foci Induced by Ionizing Radiation and DNA Cross-Linking Agent Mitomycin C

Recombinational DNA Repair in Cancer and Normal Cells: The Challenge of Functional Analysis

Regulation of repair by the 26S proteasome

Nucleotide Excision Repair, Genome Stability, and Human Disease: New Insight from Model Systems

Ku and the Stability of the Genome

DNA Damage, Repair, and Diseases

Werner Syndrome

Answering the Call: Coping with DNA Damage at the Most Inopportune Time