Abstract
BackgroundThe observation that germline mutations in the oxidative DNA damage repair gene MUTYH cause colorectal cancer (CRC) provides strong evidence that dysregulation of the base excision repair (BER) pathway influences disease susceptibility. It is conceivable that germline sequence variation in other BER pathway genes such as NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 also contribute to CRC susceptibility.MethodsTo evaluate whether sequence variants of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes might act as CRC susceptibility alleles, we screened the coding sequence and intron-exon boundaries of these genes in 94 familial CRC cases in which involvement of known genes had been excluded.ResultsThree novel missense variants were identified NEIL2 C367A, TDG3 A196G and UNG2 C262T in patients, which were not observed in 188 healthy control DNAs.ConclusionWe detected novel germline alterations in NEIL2, TDG and UNG patients with CRC. The results suggest a limited role for NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 in development of CRC.
Highlights
The observation that germline mutations in the oxidative DNA damage repair gene MUTYH cause colorectal cancer (CRC) provides strong evidence that dysregulation of the base excision repair (BER) pathway influences disease susceptibility
The BER pathway plays a pivotal role in protecting against oxidative DNA damage and is especially relevant in colorectum, which is characterised by high levels of oxygen radicals generated by bacteria and dietary carcinogens [5,6]
These include endonuclease IIIlike 1 (NTHL1, MIM 602556) which acts on oxidized pyrimidine residues; endonuclease VIII-like 1 (NEIL1, MIM 608844) and endonuclease VIII-like 2, (NEIL2, MIM 608933) which initiate the first step in BER by cleaving reactive oxygen species (ROS) damaged bases; N-methylpurine DNA glycosylase (MPG; MIM 156565) which removes a diverse group of damaged bases, including cytotoxic and mutagenic alkylation adducts of purine; thymine-DNA glycosylase (TDG, MIM 601423) which initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties; uracil-DNA glycosylase (UNG, MIM 191525) which removes uracil in DNA resulting from deamination of cytosine or replicative incorporation of dUMP, and single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1; MIM 607753) which removes uracil from single- and double-stranded DNA in nuclear chromatin
Summary
The observation that germline mutations in the oxidative DNA damage repair gene MUTYH cause colorectal cancer (CRC) provides strong evidence that dysregulation of the base excision repair (BER) pathway influences disease susceptibility. In addition to MUTYH a number of other DNA glycosylases participate in BER These include endonuclease IIIlike 1 (NTHL1, MIM 602556) which acts on oxidized pyrimidine residues; endonuclease VIII-like 1 (NEIL1, MIM 608844) and endonuclease VIII-like 2, (NEIL2, MIM 608933) which initiate the first step in BER by cleaving reactive oxygen species (ROS) damaged bases; N-methylpurine DNA glycosylase (MPG; MIM 156565) which removes a diverse group of damaged bases, including cytotoxic and mutagenic alkylation adducts of purine; thymine-DNA glycosylase (TDG, MIM 601423) which initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties; uracil-DNA glycosylase (UNG, MIM 191525) which removes uracil in DNA resulting from deamination of cytosine or replicative incorporation of dUMP, and single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1; MIM 607753) which removes uracil from single- and double-stranded DNA in nuclear chromatin
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