How chromosomes are protected from dangerous fusion
Chromosomes in the cell nucleus do not merge with each other, but such catastrophes would occur regularly if it were not for a protein known as TRF2. Scientists at the Scripps Research Institute have deciphered the key components of the mechanism by which this protein performs its protective function. These data are a significant achievement for cell biology: they will help to better understand the processes of cell malignancy and aging of the body.
According to the head of the study, Associate Professor Eros Lazzerini Denchi, cells recognize the end sections of chromosomes as DNA damage zones, and without the TRF2 protein they would inevitably attempt to repair the damage by merging two chromosomes. Previously, it was assumed that TRF2 plays a passive role, consisting in hiding the terminal fragments of chromosomes from intracellular DNA repair systems. However, it turned out that this protein actively suppresses cellular reactions aimed at restoring such false damages.
TRF2 is a part of protective protein groups localized at the end sites of chromosomes – telomeres. Telomeres shorten during each cell division and lose the TRF2 protein when they reach a critical length. This leads to the launch of DNA damage repair mechanisms that connect chromosomes deprived of protective groups to each other. The result of this is the death of cells or, in some cases, their uncontrolled division, leading to the formation of a malignant tumor.
In 2007, Denchy discovered that one of the mechanisms of action of TRF2 is the blocking of a certain signaling mechanism involved in triggering the process of repairing DNA damage. As part of the latest work, which he and his colleagues devoted to a more detailed study of the protective functions of this protein, scientists found that the TRF2 protein uses a two-component mechanism to protect the end sections of chromosomes.
The TRF2 molecule consists of four functional domains, the functions of each of which were analyzed by creating variants of a protein molecule in which one or more functional domains were replaced by non-functional components. Studying the behavior of such artificial proteins in the cell allowed scientists to differentiate the functions of individual TRF2 protein domains.
It turned out that two domains perform independent roles in suppressing reactions aimed at repairing DNA damage. One of them, TRFH, blocks the first stage of triggering the DNA repair mechanism – localization of the DNA damage factor known as gammaH2AX. This is achieved by structural modification of the telomere, providing its "shelter" from the DNA damage repair system. Another region of the TRF2 protein, called iDDR (from the English "inhibitor of the DNA damage response pathway" – an inhibitor of the DNA damage repair mechanism), independently actively suppresses the transmission of a DNA damage signal to the components of the corresponding signaling mechanism located below gammaH2AX.
The effects of the iDDR domain are partly due to the launch of enzymatic activity associated with the BRCA1 tumor suppressor gene. Defects in this gene are associated with incorrect repair of DNA damage, genome instability and an extremely high risk of cancer. (Certain mutations of the BRCA1 gene increase the risk of developing breast or ovarian cancer over a lifetime by more than 50%.) New data suggest that BRCA1 defects can also lead to a decrease in the effectiveness of telomere protection.
Currently, the authors are planning experiments on cell lines and transgenic mice, which will allow them to further delve into the mechanisms of TRF2 functioning, especially in aspects of its relationship with the activity of the BRCA1 gene.
Article by Keiji Okamoto et al. A two-step mechanism for TRF2-mediated chromosome-end protection is published in the journal Nature.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Scripps Research Institute:
Scripps Research Institute Scientists Discover How Chromosomes Keep Their Loose Ends Loose.
07.02.2013