Guanine Holes Are Prominent Targets for Mutation in Cancer and Inherited Disease

Abstract

Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G•C bp in the context of all 64 5′-NGNN-3′ motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.

Hypermutation in human cancer genomes: footprints and mechanisms

“…Highly mutagenic 8-oxo-7,8 dihydroguanine (8-oxoG) could be the reason for such a bias, however other products of reactions of guanine and cytosine could also contribute 94 . Vasquez and colleagues 99, 100 found the mutation motif [(A|T|G|C)(T|C) C (A|T|C)]) is enriched in several cancers. Experimentally, they found that guanines in the complementary sequence context have a higher potential to trap electrons and thus have an increased chance of chemical modification.…”

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

“…Model for base‐pair substitutions at quadruplex DNA. – e – , electron loss; although sites of electron loss are known to occur anywhere along a DNA molecule, they tend to delocalize and come to rest preferentially at sites of lowest ionization potentials (charge transfer; hole migration), such as at the 5′ G of GG and GGG runs [Margolin et al., ; Bacolla et al., ; Morikawa et al., ]. The effect of charge transfer is not included in the model for the sake of clarity.…”

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

“…Our structural analyses of the p.A1065T mutation show that it is located in the activation loop, close to key active site residues, and able to impact protein function by interrupting the inactive conformation of VEGFR2. The codon for the A1065 amino acid residue is also in a splice region at the border of intron-exon 24, and based on the known donor/acceptor patterns 25 the c.3193C>T change might cause a splice variant. However the acceptor site is unlikely altered, since alignments of homologous VEGFR sequences show that the VEGFR1 protein (FLT1 gene) contains a naturally occurring threonine residue, p.T1059, also found in exon 24, and has the same sequence context in the splicing region.…”