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If a gene necessary for DNA repair is hypermethylated, resulting in deficient DNA repair, DNA damages will accumulate. Increased DNA damage tends to cause increased errors during DNA synthesis, leading to mutations that can give rise to cancer. If hypermethylation of a DNA repair gene is an early step in carcinogenesis, then it may also occur ...
The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis. DNA damage is considered to be the primary cause of cancer. [17] More than 60,000 new naturally-occurring instances of DNA damage arise, on average, per human cell, per day, due to endogenous cellular processes (see article DNA damage (naturally occurring)).
Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations ...
Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, XRCC1 mediated MMEJ repair is directly mutagenic, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
The most significant role of MSH3 in cancer is the suppression of tumors by repair of somatic mutations in DNA that occur as the result of base-base mispairs and insertion/deletion loops. Both loss of expression and over expression of MSH3 can lead to carcinogenic effects.
Hereditary non-polyposis colon cancer, also known as Lynch syndrome, is an autosomal dominant cancer syndrome that increases the risk of colorectal cancer. It is caused by genetic mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2. In addition to colorectal cancer many other cancers are increased in frequency.
The schematic diagram indicates the roles of insufficient DNA repair in aging and cancer, and the role of apoptosis in cancer prevention. An excess of naturally occurring DNA damage, due to inherited deficiencies in particular DNA repair enzymes, can cause premature aging or increased risk for cancer (see DNA repair-deficiency disorder).
MGMT (O-6-methylguanine-DNA methyltransferase) is an important cancer biomarker because it is involved in the repair of DNA damage and is often silenced or inactivated in cancer cells. The loss of MGMT function leads to a higher rate of mutations, promoting the formation and progression of tumors.