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Analysis of the 5' region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene
N C Nicolaides1, K W Kinzler, B Vogelstein
1Howard Hughes Medical Institute, Baltimore, Maryland 21231, USA.
Abstract:
The PMS2 gene encodes a protein that is involved in DNA mismatch repair and is mutated in a subset of patients with hereditary nonpolyposis colon cancer (HNPCC). The previously published PMS2 cDNA sequence lacks an upstream in-frame stop codon preceding the presumptive initiating methionine. To evaluate the 5' terminus of the PMS2 coding region further, we isolated additional cDNA clones, RT-PCR products, and the corresponding 5' genomic segment of the PMS2 locus. The PMS2 gene transcripts were found to have heterogeneous but colinear 5' termini, one of which contained an in-frame termination codon preceding the initiating methionine. In addition, a novel gene encoding a 34.5-kDa polypeptide was found to initiate transcriptionally within PMS2 from the opposite strand.
Insights
The PMS2 gene
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The PMS2 gene is crucial for DNA mismatch repair, and its mutations are linked to hereditary nonpolyposis colon cancer (HNPCC).
- Previous studies indicated a potential issue with the PMS2 cDNA sequence regarding an upstream in-frame stop codon.
Purpose of the Study:
- To investigate the 5' terminus of the PMS2 coding region and its implications for gene function.
- To clarify the transcriptional start sites and potential regulatory elements of the PMS2 gene.
Main Methods:
- Isolation and analysis of additional cDNA clones and RT-PCR products.
- Sequencing of the 5' genomic segment of the PMS2 locus.
- Characterization of PMS2 gene transcripts.
Main Results:
- PMS2 gene transcripts exhibit heterogeneous but colinear 5' termini.
- One identified transcript contains an in-frame termination codon upstream of the initiating methionine.
- A novel gene encoding a 34.5-kDa polypeptide initiates transcription within PMS2 from the opposite strand.
Conclusions:
- The findings clarify the complex transcriptional landscape of the PMS2 gene.
- The presence of alternative start sites and a novel overlapping gene may influence PMS2 function and its role in HNPCC.