Why the DNA self-depurination mechanism operates in HB-β but not in β-globin paralogs HB-δ, HB-ɛ1, HB-γ1 and HB-γ2
| Autor: | Juan R. Alvarez-Dominguez, Jacques R. Fresco, Olga Amosova |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Guanine
Base pair Base Pair Mismatch Health Toxicology and Mutagenesis Molecular Sequence Data beta-Globins Biology Catalysis Conserved sequence Evolution Molecular chemistry.chemical_compound Species Specificity hemic and lymphatic diseases Sequence Homology Nucleic Acid Genetics Animals Humans Point Mutation gamma-Globins Globin Codon Molecular Biology Gene Conserved Sequence delta-Globins Base Sequence DNA Molecular biology Hemoglobinopathies chemistry Duplex (building) Coding strand Vertebrates Depurination Nucleic Acid Conformation Sequence Alignment |
| Zdroj: | Mutation research. 778 |
| ISSN: | 1873-135X |
| Popis: | The human β-globin, δ-globin and ɛ-globin genes contain almost identical coding strand sequences centered about codon 6 having potential to form a stem-loop with a 5′GAGG loop. Provided with a sufficiently stable stem, such a structure can self-catalyze depurination of the loop 5′G residue, leading to a potential mutation hotspot. Previously, we showed that such a hotspot exists about codon 6 of β-globin, with by far the highest incidence of mutations across the gene, including those responsible for 6 anemias (notably Sickle Cell Anemia) and β-thalassemias. In contrast, we show here that despite identical loop sequences, there is no mutational hotspot in the δ- or ɛ1-globin potential self-depurination sites, which differ by only one or two base pairs in the stem region from that of the β-globin gene. These differences result in either one or two additional mismatches in the potential 7-base pair-forming stem region, thereby weakening its stability, so that either DNA cruciform extrusion from the duplex is rendered ineffective or the lifetime of the stem-loop becomes too short to permit self-catalysis to occur. Having that same loop sequence, paralogs HB-γ1 and HB-γ2 totally lack stem-forming potential. Hence the absence in δ- and ɛ1-globin genes of a mutational hotspot in what must now be viewed as non-functional homologs of the self-depurination site in β-globin. Such stem-destabilizing variants appeared early among vertebrates and remained conserved among mammals and primates. Thus, this study has revealed conserved sequence determinants of self-catalytic DNA depurination associated with variability of mutation incidence among human β-globin paralogs. |
| Databáze: | OpenAIRE |
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