Researchers have discovered a repetitive and highly variable DNA sequence that regulates telomerase activity, illuminating a genetic and molecular basis of human ageing and cancer susceptibility.
The role of telomerase in ageing
The intricacies behind human ageing have mystified scientists for centuries. With advancements in genetics research, telomere shortening is now widely known as a hallmark of ageing. Telomeres form the ends of chromosomes and maintain chromosomal stability. In humans, they shorten each time somatic cells divide and thus act as a clock for cellular senescence.
Telomere shortening is offset by human telomerase reverse transcriptase (hTERT), which elongates telomeres and regulates telomere length homeostasis. hTERT is highly expressed during embryonic development and in stem cell-rich tissues, but less so in the majority of differentiated adult tissues.
Recent studies have shown that hTERT is overexpressed in cancer cells, contributing to their capacity for limitless replication. The hTERT locus harbours many cancer-associated mutations and can thus serve as a therapeutic target. Yet, the mechanisms of hTERT transcriptional control remain unknown.
A novel driver of telomerase
Recently, researchers from Washington State University identified a DNA region that drives hTERT activity, known as VNTR2-1. Their findings, published in PNAS, have revealed a novel molecular basis for human ageing and tumourigenesis.
VNTR2-1 is an intronic, enhancer-like regulatory element located outside of the hTERT promoter. It consists of numerous 42-basepair repeats, with hTERT seeming to be more active with a longer VTNR2-1 sequence.
In the study, in vitro VNTR2-1 deletions in human and mouse cancer cells resulted in reduced hTERT mRNA expression and telomerase activity levels. The cells exhibited progressive telomere shortening, accelerated ageing and impaired tumour growth. On the other hand, the deletions did not alter hTERT transcription in undifferentiated stem cells. These observations indicate that VNTR2-1 is crucial for hTERT transcription and may be involved in maintaining telomerase expression in somatic stem cells.
VNTR2-1 variation in human populations
Given that hTERT polymorphisms have been associated with human longevity and age-related diseases, VNTR2-1 allele variation may represent a molecular and genetic basis for ageing and differential disease susceptibility in different populations.
To test this hypothesis, researchers sequenced the VNTR2-1 region in Caucasian and African American centenarians and controls from the Georgia Centenarian Study. Centenarians were 98 to 108 years of age while controls were 20 to 59 years old.
They found that VNTR2-1 repeat length is strictly conserved at 42-basepairs, with only minor sequence variations. VNTR2-1 repeat numbers varied greatly, ranging from 53 to 160 repeats.
Only African American centenarians harboured short VNTR2-1 sequences with a length of 53 to 73 repeats. Notably, significantly fewer centenarians carried short VNTR2-1 alleles relative to controls in the African American population. This suggests that VNTR2-1 plays an important role in human ageing. Although a shorter allele seems to reduce telomerase activity, it does not necessarily result in a shorter lifespan. Instead, it could mean that an individual is less likely to develop cancer.
VNTR2-1 polymorphisms may therefore contribute to the genetic diversity underlying human ageing and age-related tumourigenesis. Not only do these findings reveal a potential therapeutic target for cancer, but they also provide a major clue towards solving an age-old mystery.
Image credit: Rost-9D – Getty Images (via Canva)
