Abstract
Transcripts of many enzymes involved in base excision repair (BER) undergo extensive alternative splicing, but functions of the corresponding alternative splice variants remain largely unexplored. In this review, we cover the studies describing the common alternatively spliced isoforms and disease-associated variants of DNA glycosylases, AP-endonuclease 1, and DNA polymerase beta. We also discuss the roles of alternative splicing in the regulation of their expression, catalytic activities, and intracellular transport.
Highlights
Base excision repair (BER) is the predominant and conserved pathway that corrects small DNA lesions derived from oxidation, deamination, and alkylation
We address alternative splicing of key base excision repair (BER) enzymes: DNA glycosylases, APEX1, and Pol β
Transcripts encoding BER enzymes undergo extensive alternative splicing that serves diverse purposes. It leads to production of proteins with grossly different catalytic capacity compared with their major annotated isoform, regulates their intracellular transport, or provides a post-transcriptional regulation mechanism
Summary
Base excision repair (BER) is the predominant and conserved pathway that corrects small DNA lesions derived from oxidation, deamination, and alkylation (reviewed in [1,2,3,4,5]). Three mRNA isoforms are synthesized, two encoding identical polypeptides (MUTYHα) homologous to the major human isoform, while the third uses an alternative translation initiation site and skips one internal exon, resulting in a protein lacking the DNA minor groove-binding motif and likely inactive [122]. In addition to mRNA encoding full-length NEIL1, two splice variants were detected, one containing full intron 4, another including the first 10 nt of intron 1 Both variants produce truncated proteins, which lack fully or partially the C-terminal DNA-binding domain and possess no catalytic activity [154]. The APEX1 gene contains five exons and produces four mRNA isoforms that differ by using splice donor sites in the untranslated exon 1 and all produce the same polypeptide [44,162,163,164,165,166,167,168,169,170,171,172]
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