Biology Reference
In-Depth Information
TABLE 8.1 Phenotypes of Mouse Strains Carrying Knockout Mutations of NHEJ Genesdcont'd
Genotype
Tumors
Other observations
References
Malignant glioma
Lack of
Artemis
accelerates loss of
heterozygosity of
p53
XLF
/
No tumors
Normal size
Modest decrease in lymphocyte numbers
Impaired V(D)J recombination
MEFs are radiosensitive
315
XLF
/
p53
/
Thymic lymphoma
medulloblastoma in situ
315
their 3
0
and 5
0
flanking regions and in the non-coding
regions. Those in the coding region may be harmless
or cause a potentially deleterious change to the protein
function. SNPs in the flanking regions may alter
a gene's expression and consequently alter the quantity
of the protein coded by the gene.
It is important to point out that SNPs may serve as
a marker of a particular disease phenotype without
having any direct impact on the disease. This is due to
the phenomenon of linkage disequilibrium, which refers
to a non-random inheritance of two alleles.
230
Several studies have focused on SNPs in DNA repair
genes including the NHEJ gene family. Examples
include SNPs in
XRCC4
and
LIG4
that have been
associated with increased susceptibility to non-small
cell lung cancer in Taiwan,
231,232
XRCC4
and
Ku80
to
bladder cancer in Spain and Taiwan,
233
e
235
XRCC4
,
LIG4
,
Ku70
, and
Ku80
to breast cancer in US and
Belgian women,
236,237
XRCC4
,
LIG4
, and
DNA-PKcs
to glioma,
238,239
and
LIG4
to multiple myeloma.
240
A variety of SNPs were analyzed in these studies,
including exonic, intronic and 3
0
- and 5
0
-untranslated
regions. These studies support the hypothesis that low
penetrance polymorphisms in NHEJ genes play a role
in the induction of various tumors. Furthermore, some
of the studies indicated a trend of increased risk of
tumor induction with increasing SNPs in the NHEJ
genes, suggesting an additive or even synergistic effect
of multiple NHEJ genetic variants. In their study,
Willems
et al.
237
observed that some of the variant alleles
of
Ku70
and
Ku80
correlated with both breast cancer
predisposition and
in vitro
chromosomal radiosensi-
tivity. Similar studies of DNA repair capacity based on
DNA end-joining assays or direct assays of DNA-PK
activity using cell extracts from peripheral blood
lymphocytes isolated from patients and control subjects
support a role for NHEJ in protection against lung and
breast cancer.
241
e
243
An emerging area of interest is the potential regulation
of DNA repair genes by epigenetic mechanisms such as
of the DSB induction during V(D)J recombination.
A broader issue is the role of NHEJ in protection against
the development of sporadic tumors in the general pop-
ulation. A number of factors can contribute to lower
NHEJ activity, including reduced expression at the tran-
scriptional level due to gene dosage effects or disrupted
transcriptional regulation, and lower protein activity,
due to reduced protein levels or production of mutated
protein.
ATM
was one of the first genes to be associated
with general cancer risk. Swift and colleagues
225
noted
that AT heterozygous carriers comprise about 1% of
the general population, and reasoned that if AT carriers
display an intermediate cancer predisposition between
normal and AT homozygotes, they could constitute
a reasonably high percentage of the population at
elevated risk of cancer. Although this was a contentious
issue for many years, there is now general consensus
that AT heterozygosity carries approximately two-fold
increased risk for cancer, especially breast cancer.
226,227
Of the other NHEJ genes, only heterozygous carriers
of mutated
NBS1
have been shown to have increased
cancer presdisposition.
216
For example, a recently iden-
tified
NBS1
heterozygous mutation, which results in the
loss of the MRE11- and ATM-binding site in the carboxy
terminus of the NBS1 protein, was identified in 2% of
gastric cancer patients (96 individuals) but in only
0.09% of over 2000 control subjects in a Japanese
population.
228
There is now a major emphasis to link single nucle-
otide polymorphisms (SNPs) with increased cancer
risk. A SNP, as the term suggests, is a variation in the
DNA sequence at the single nucleotide level found
between members of a species or paired chromosomes
in an individual. SNPs comprise approximately 0.1% of
the human genome.
229
SNPs usually only have two
alleles, a more common major allele and a less frequent
minor allele, and each person will be either homozy-
gous for the major allele or minor allele, or heterozy-
gous for the major/minor alleles. SNPs are found
throughout the genome; in the coding regions of genes,
