Scientists home in on the mechanism that protects cells from premature aging

Molecules that accumulate on the tip of chromosomes are recognized to play a key function in stopping injury to our DNA. Now, researchers at EPFL have unraveled how these molecules house in on particular sections of chromosomes—a discovering that might assist to raised perceive the processes that regulate cell survival in growing older and most cancers.

Very similar to the aglet of a shoelace prevents the tip of the lace from fraying, stretches of DNA referred to as telomeres kind protecting caps on the ends of chromosomes. However as cells divide, telomeres change into shorter, making the protecting cap much less efficient. As soon as telomeres get too quick, the cell stops dividing. Telomere shortening and malfunction have been linked to cell growing older and age-related diseases, together with most cancers.

Scientists have recognized that RNA species referred to as TERRA assist to control the size and performance of telomeres. Found in 2007 by postdoc Claus Azzalin within the crew of EPFL Professor Joachim Lingner, TERRA belongs to a category of molecules referred to as noncoding RNAs, which aren’t translated into proteins however operate as structural elements of chromosomes. TERRA accumulates at chromosome ends, signaling that telomeres ought to be elongated or repaired.

Nevertheless, it was unclear how TERRA acquired to the tip of chromosomes and remained there. “The telomere makes up solely a tiny little bit of the overall chromosomal DNA, so the query is ‘how does this RNA discover its house?'” Lingner says. To handle this query, postdoc Marianna Feretzaki and others within the groups of Joachim Lingner at EPFL and Lumir Krejci at Masaryk College got down to analyze the mechanism by which TERRA accumulates at telomeres, in addition to the proteins concerned on this course of. The findings are printed in Nature.

Discovering house

By visualizing TERRA molecules beneath a microscope, the researchers discovered {that a} quick stretch of the RNA is essential to deliver it to telomeres. Additional experiments confirmed that after TERRA reaches the tip of chromosomes, a number of proteins regulate its affiliation with telomeres. Amongst these proteins, one referred to as RAD51 performs a very vital function, Lingner says.

RAD51 is a well known enzyme that’s concerned within the restore of damaged DNA molecules. The protein additionally appears to assist TERRA stick with telomeric DNA to kind a so-called “RNA-DNA hybrid molecule”. Scientists thought this sort of response, which results in the formation of a three-stranded nucleic acid construction, primarily occurred throughout DNA restore. The brand new research exhibits that it might probably additionally occur at chromosome ends when TERRA binds to telomeres. “That is paradigm-shifting,” Lingner says.

The researchers additionally discovered that quick telomeres recruit TERRA far more effectively than lengthy telomeres. Though the mechanism behind this phenomenon is unclear, the researchers hypothesize that when telomeres get too quick, both resulting from DNA injury or as a result of the cell has divided too many occasions, they recruit TERRA molecules. This recruitment is mediated by RAD51, which additionally promotes the elongation and restore of telomeres. “TERRA and RAD51 assist to forestall unintentional loss or shortening of telomeres,” Lingner says. “That is an vital operate.”

Given the function of telomeres in well being and illness, it will likely be vital to see how the newly found mechanism—which was deduced from observations in dwelling cells and reproduced in check tubes—is regulated within the very advanced mobile atmosphere, Lingner says. “We put ahead a mannequin, which is supported by the info we’ve got—however usually in science, it seems that the mannequin should be modified,” he says. “There can definitely be further surprises.”

Subsequent, his crew plans to handle different key questions, together with whether or not RAD51 mediates the affiliation of different noncoding RNAs with chromosomes. The researchers additionally intention to raised characterize the equipment that mediates the affiliation of TERRA with chromosomes, and work out the features that this affiliation allows. “There are quite a lot of questions that stay open,” Lingner says.