The TERT-CLPTM1L region of chromosome 5p15.33 is a multi-
cancer susceptibility locus that encodes the
reverse transcriptase subunit, hTERT, of the
telomerase enzyme. Numerous
cancer-associated single-nucleotide polymorphisms (SNPs), including rs10069690, have been identified within the hTERT gene. The minor allele (A) at rs10069690 creates an additional
splice donor site in intron 4 of hTERT, and is associated with an elevated risk of multiple
cancers including breast and ovarian
carcinomas. We previously demonstrated that the presence of this allele resulted in co-production of full length (FL)-hTERT and an alternatively spliced, INS1b, transcript. INS1b does not encode the
reverse transcriptase domain required for
telomerase enzyme activity, but we show here that INS1b
protein retains its ability to bind to the
telomerase RNA subunit, hTR. We also show that INS1b expression results in decreased
telomerase activity, telomere shortening, and an increased telomere-specific DNA damage response (DDR). We employed
antisense oligonucleotides to manipulate endogenous transcript expression in favor of INS1b, which resulted in a decrease in
telomerase activity. These data provide the first detailed mechanistic insights into a
cancer risk-associated SNP in the hTERT locus, which causes cell type-specific expression of INS1b transcript from the presence of an additional
alternative splice site created in intron 4 by the risk allele. We predict that INS1b expression levels cause subtle inadequacies in
telomerase-mediated telomere maintenance, resulting in an increased risk of genetic instability and therefore of
tumorigenesis.