Diseases Associated with Nucleic Acid Metabolism

❖In addition to proofreading, cells have other repair systems for preventing
mutations due to copying errors and exposure to mutagens.
❖Several DNA repair systems that normally operate with a high degree of
accuracy have been well studied.
▪ These systems were first elucidated through a combination of genetic and
biochemical studies in E. coli.
❖Homologs of the key bacterial proteins exist in eukaryotes from yeast to
humans, indicating that these error-free mechanisms arose early in evolution
to protect DNA integrity. 1
Diseases Associated with Nucleic Acid Metabolism Contd.
Mechanism of DNA Repair

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Diseases Associated with Nucleic Acid Metabolism Contd.
❖Each of these systems functions in a similar manner—a segment of the
damaged DNA strand is excised, and the gap is filled by DNA polymerase
and ligase using the complementary DNA strand as template.
❖Defects in DNA-repair systems or loss of this system are expected to increase
the overall frequency of mutations and, hence, the likelihood of a cancer-
causing mutation.
❖For example, humans who inherit mutations in genes that encode a crucial
mismatch-repair or excision-repair protein have an enormously increased
probability of developing certain cancers. 3
Some Human Hereditary Diseases and Cancers Associated
with DNA-Repair Defects

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 Xeroderma Pigmentosum
❖Xeroderma pigmentosum, a rare human skin disease, is genetically transmitted as an
autosomal recessive trait.
❖The skin in an affected homozygote is extremely sensitive to sunlight or ultraviolet
light.
❖In infancy, severe changes in the skin become evident and worsen with time; the skin
becomes dry, and there is a marked atrophy of the dermis; keratoses appear and the
eyelids become scarred.
❖Skin cancer usually develops at several sites; the risk of developing skin cancer is
increased 1000- to 2000-fold.
❖Many patients die before age 30 from metastases of these malignant skin tumors.5
 Xeroderma Pigmentosum Contd.
❖Ultraviolet light produces pyrimidine dimmers (especially thymine
dimmers) in human DNA, as it does in E. coli DNA.
❖Cells cultured from patients with xeroderma pigmentosum exhibit low
activity for the nucleotide excision-repair process.
❖In normal fibro-blasts, half the pyrimidine dimmers produced by ultraviolet
radiation are excised in less than 24 hours.
❖In contrast, almost no dimers are excised in this time interval in fibroblasts
derived from patients with xeroderma pigmentosum.
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 Xeroderma Pigmentosum Contd.
❖The results of these studies show that xeroderma pigmentosum can be
produced by a defect in the excinuclease (excision endonuclease) that
hydrolyzes the DNA backbone near a pyrimidine dimer.
❖The drastic clinical consequences of this enzymatic defect emphasize the
critical importance of DNA-repair processes.
❖The disease can also be caused by mutations in eight other genes for DNA
repair, which attests to the complexity of repair processes.

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 Hereditary Nonpolyposis Colorectal Cancer

❖Defects in other repair systems can increase the frequency of other

tumors.
❖For example, hereditary nonpolyposis colorectal cancer (HNPCC, or
Lynch syndrome) results from defective DNA mismatch repair.
❖HNPCC is not rare as many as 1 in 200 people will develop this form of
cancer.
❖Mutations in two genes, called hMSH2 and hMLH1, account for most
cases of this hereditary predisposition to cancer.
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 Hereditary Nonpolyposis Colorectal Cancer Contd.
❖The striking finding is that these genes encode the human counterparts of MutS
and MutL of E. coli.
❖The MutS protein binds to mismatched base pairs (e.g., G-T) in DNA.
❖An MutH protein, together with MutL, participates in cleaving one of the DNA
strands in the vicinity of this mismatch to initiate the repair process.
❖It seems likely that mutations in hMSH2 and hMLH1 lead to the accumulation
of mutations throughout the genome.
❖In time, genes important in controlling cell proliferation become altered,
resulting in the onset of cancer.
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