A functional component of telomeres called TERRA has to constantly be kept in check to prevent telomeric and chromosomal instability, according to researchers from Instituto de Medicina Molecular (iMM) João Lobo Antunes.
Telomeres, the very ends of linear chromosomes, protect the stability of genomes by preventing erosion of genetic material and fusion of independent chromosomes. When telomeres are dysfunctional, severe genomic instability arises and features of dysfunctional telomeres are often observed in cancer cells as well as in aged cells.
In research published today in Nature Communications, a team led by Claus Azzalin, wanted to understand whether TERRA could become dangerous if not properly maintained in cells.
They found an interplay between three key telomeric molecules—the long noncoding RNA TERRA and two telomeric proteins, TRF1 and TRF2. While TRF2 is able to promote the formation of RNA: DNA hybrids between TERRA and telomeric DNA, TRF1 prevents this TRF2 associated activity. When this interplay is compromised the ensuing RNA: DNA hybrid structures lead to loss of telomeres and therefore genome instability.
These results show that telomeres in general and, more specifically TERRA, need to be constantly regulated to serve their protective functions. Indeed, a lack of such fine regulation leads to severe telomere (and chromosomal) instability.
These discoveries could help understand the molecular basis of chromosomal instabilities associated with cancer development and age-associated diseases possibly paving the way for new therapeutic approaches.
"I expect this study will open a new window on our understanding of genome stability and ultimately help in the development of aging and cancer therapies" said the study's first author Yong Woo Lee.