Structural intermediates of deletion mutagenesis: a role for palindromic DNA.

Abstract

A model is presented for deletion mutations whose formation is mediated by palindromic and quasipalindromic DNA sequences. It proposes that the self-complementarity of palindromes allows the formation of DNA secondary structures that serve as deletion intermediates. The structures juxtapose the end points of the deletion and thus direct deletion specificity. While misaligned DNA intermediates that explain deletion termini occurring in repeated DNA sequences have been described, no explanations have been offered for deletion termini occurring in other sequences. The DNA secondary structures whose formation is mediated by palindromic sequences appear to explain many of these. In this paper, secondary-structure intermediates are described for a series of spontaneous deletions of known sequence in the lad gene of Escherichia coli. The model is supported by its failure to predict structures that can juxtapose simulated deletion termini in the lacI gene. We have found a strong association between palindromic sequences and repeated sequences at lacl deletion termini that suggests the joint participation of repeated and palindromic DNA sequences in the formation of some deletions. Sequences of deletions in other organisms also suggest the participation of palindromic DNA sequences in the formation of deletions.Local DNA sequences can strongly influence the frequency of mutation (1). The frequent association of deletion termini with repeated DNA sequences (2-4) suggests that deletion mutations are no exception. The In its simplest form, our model proposes that DNA secondary structures whose formation is potentiated by palindromic or quasipalindromic DNA sequences participate in deletion formation through the juxtaposition of deletion end points. The inherent self-complementarity of palindromic DNA sequences permits the formation of cruciform or hairpin structures in nucleic acids, precisely juxtaposing otherwise distant bases (6). Repeated DNA sequences are not required.The termini of the E. coli lacd deletion S86 cannot be juxtaposed by a misalignment involving repeated sequences. However, the deletion termini are located precisely at the ends of a quasipalindromic DNA sequence that includes the entire deletion. The formation of a DNA hairpin or cruciform structure in the wild-type DNA sequence places the deletion termini immediately adjacent to one another, rather than separated by their normal linear distance of 27 base pairs (Fig. 1A). This structural intermediate would produce the S86 deletion if it served as a substrate for excision or as a template for DNA synthesis (Fig. 1B). The latter process might be mediated by either DNA polymerase or DNA ligase. A ligation across such a hairpin stem might also be responsible for deletions if the hairpin served as a substrate for nucleases that removed aberrantly aligned regions from ordinary double-stranded DNA. Whatever the precise molecular mechanism(s) responsible for the production of deletions from such DNA structures, the prediction of the model is that the ...

The human and mouse orthologous LIM-only proteins respectively encoded in chromosome 6 and 17 show a different expression pattern

“…Such a process has been observed in other instances such as in deletion mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in human T lymphocytes [30] or in deletions in the APRT gene of Chinese hamster ovary cells [31]. Glickman and Ripley [32] have proposed a model to explain deletion mutations in which palindromic and quasipalindromic DNA sequences enable the formation of secondary structures that are removed by deletion. In the human and mouse CRP sequences, the polypeptide LSPS(S/N)FSPPRPRTGL found in the linker portion of the human and mouse proteins is divergent from the three known CRPs.…”

Mutagenesis by hydrogen peroxide treatment of mammalian cells: a molecular analysis

“…This observation was later found to hold for much larger spontaneous deletions (700-lOOO bp) in this same gene (30). Further analysis of such deletion data (31) showed that of those deletions which did not involve repeated DNA sequences, the majority contained palindromic or quasi-palindromic sequences capable of forming secondary structures that could juxtapose the end points of the deleted region and in this way direct the deletion specificity. Thus, in the latter case repeated DNA sequences are not required.…”

Identification of secondary structure in the 5′-untranslated region of the human adrenomedullin mRNA with implications for the regulation of mRNA translation

“…Furthermore, the 65 bp sequence is part of exon 1 sequence in AM gene and unlikely to be deleted by alternative splicing events. Mechanisms accounting for the ability of a polymerase copying a template to skip a region and then resume faithful transcription of the remainder of the sequence have been proposed by others to explain internal deletions occuring during DNA synthesis by DNA polymerase (Glickman and Ripley, 1984;Cariello et al, 1991;Odelberg et al, 1995;Canceill and Ehrlich, 1996). In all cases, these models require that the deleted sequence contains a region of stable secondary structure.…”