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Short direct repeats flanking deletions, and duplicating insertions in p53 gene in human cancers
Abstract:
Compilation of 740 independent p53 mutations from a wide variety of human cancers was performed between 1989 and April 1992. Deletions or insertions were observed in 10% of the cases. Insertions ranged from 1 to 14 nucleotides. In 14 out of 16 cases, the inserted nucleotide(s) duplicated the sequence where it was inserted. The deletions ranged from one to 37 nucleotides. Twenty six cases were single nucleotide deletions and 19 of them were localized at iterated nucleotides. In all 26 deletions of two nucleotides or more, a direct repeat of 2-8 base pairs was present on the unaltered sequence in the close vicinity of the deletion. In 15 of these cases, the deletion removed a complete repeat and the entire region in between repeats. In the remaining cases, the deletion imperfectly removed one or both repeats and/or the intercalating sequence. Both p53 insertions and deletions can be explained by a slipped-mispairing mechanism as proposed for germinal mutations of a small number of eukaryotic genes. Less frequent than the deamination of 5-methyl cytosine in CpG dinucleotides, mutations resulting in loss or gain of nucleotide base pairs may represent the second highest endogenous mutagenic event for p53 gene in human cancers.
Insights
Mutations causing insertions or deletions in the p53 gene are common in human cancers. These DNA changes, often involving repeated sequences, can be explained by slipped-mispairing, potentially being the second most frequent endogenous mutagenic event.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 tumor suppressor gene is frequently mutated in human cancers.
- Understanding the mechanisms of p53 mutations is crucial for cancer research.
Purpose of the Study:
- To analyze the types and mechanisms of p53 gene mutations involving insertions and deletions in human cancers.
- To compare the frequency of these mutations with other endogenous mutagenic events.
Main Methods:
- Compilation and analysis of 740 independent p53 mutations from various human cancers (1989-1992).
- Detailed examination of the characteristics of insertions and deletions, including their size and location.
- Investigation of sequence features associated with these mutations, such as direct repeats.
Main Results:
- 10% of analyzed p53 mutations involved insertions or deletions.
- Insertions often duplicated the target sequence, while deletions frequently occurred at iterated nucleotides or within direct repeats.
- A slipped-mispairing mechanism was proposed to explain both insertion and deletion events.
- Mutations causing nucleotide base pair loss or gain may be the second most frequent endogenous mutagenic event for p53 in cancers, after CpG deamination.
Conclusions:
- Slipped-mispairing is a likely mechanism for p53 insertions and deletions in cancer.
- These types of mutations represent a significant endogenous mutagenic pathway for the p53 gene.