Ever since it was first discovered in 1869 by Swiss chemist Friedrich Miescher, who was the first to isolate and identify a substance from cell nuclei that he termed “nuclein,” scientists and researchers have been trying to fully understand DNA. Deoxyribonucleic acid (DNA), was first coined by Albrecht Kossel in 1881, who also identified the five bases that make up DNA’s adenine, cytosine, guanine, thymine, and uracil building blocks. Soon after, Walther Flemming discovered a structure in cell nuclei that we now know as chromosomes. And most famously in 1953, James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin co-discovered the double helical structure of DNA.
Left to right: Wahyu Surya, Nikolay Korolev, Lars Nordenskiöld and Aghil Soman. Authors absent in this photo: Sook Yi Wong, Simon Lattmann, Vinod K. Vogirala, Qinming Chen, Nikolay V. Berezhnoy, John van Noort, and Daniela Rhodes
Next year, 2023, marks two important anniversaries related to DNA; it will be the 154th anniversary of its discovery and the 70th anniversary of the discovery of its double helix structure. 2022 itself marks twenty-five years since the very first high-resolution image of DNA’s nucleosome – the elementary unit for DNA packaging – was taken. However, despite the many years since DNA’s discovery, scientists are still working on unravelling some of its many mysteries.
One of those mysteries involves telomeres in chromosomes, whose structure and dynamics at the molecular level are still largely unknown. However, a team of scientists from NTU School of Biological Sciences (SBS) have discovered the first higher-order structure of telomeric chromatin, which brings us one step closer to understanding this important part of our chromosomes.
What are telomeres?
In the nuclei of your cells, DNA is tightly packaged into structures known as chromosomes, and telomeres are the structures located at the ends of these chromosomes. Made up of numerous repeating sequences of the same six nucleotides, they are essentially little protective caps that keep the ends of your chromosomes safe by preventing the loss of base pair sequences and stop your chromosomes from sticking and fusing with each other. Think of telomeres as those little plastic tips covering the ends of your shoelaces which prevent your laces from unravelling.
Telomeres are protective caps at the ends of our chromosomes. They shorten over multiple replications until the chromosomes are unable to divide further and the cell becomes inactive (senescent).
The protective nature of telomeres comes from the fact that they are ‘disposable’; they get shorter and shorter each time chromosomes divide, but by ‘sacrificing’ themselves, they prevent the loss of important genetic information. Unfortunately, the protection that telomeres offer does not last forever as they do not get replaced. Once our telomeres get too short, our chromosomes will no longer be able to divide, resulting in the cell’s inability to repair, accumulating damage and causing its eventual death. Scientists believe that the shortening of telomeres is one of the contributors to our overall ageing process.
One may bemoan this deterioration, and subsequent ageing, but this process is also our built-in cancer prevention system. In cancer cells, the telomerase enzyme keeps replacing the nucleotide sequences that make up the telomeres, effectively preventing the cancer cells from dying and causing uncontrolled cell division.
Despite the crucial role of telomeres in ageing and cancer, scientists still have limited knowledge regarding their molecular structure. Over the years, efforts to fully understand telomeres have been hindered by their low affinity (the strength of attraction between substances), stability and the repetitive nature of telomeric DNA.
NTU team sheds light on the telomeric conundrum
However, a team of scientists led by Professor Lars Nordenskiöld, Chair of SBS, and with research fellow Aghil Soman, have recently managed to shed some light on the molecular structure of telomeres in a paper published in Nature on 14 September. With help from NTU Institute of Structural Biology (NISB), the team made use of cryogenic electron microscopy – a scientific method where molecules are flash-frozen and then bombarded with electrons to produce images of individual molecules. Their discovery has provided new insights into the maintenance and function of telomeres.
The columnar structure of telomeric chromatin
The team found that telomeric chromatin formed a unique columnar structure, which is special for a couple of reasons. Firstly, it is the first higher-order structure of telomeric chromatin – where nucleosomes undergo folding to form a more complex 3D shape. Secondly, the discovery of a columnar structure that forms on natural DNA diverges from current textbook models that depict zig-zag and solenoid models (think of a wire coiled around a central axis).
Left: Nucleosomes packaged and arranged in a zig-zag model. Right: The newly discovered columnar model.
Involvement in DNA damage repair
In a typical zig-zag model, an acidic patch that is involved in nucleosome binding is usually located on the surface, where it is easily accessible. In a columnar structure, the patch is instead buried within the interior of the structure. However, the team found that damage repair at telomeres did not require an unfolding of the chromatin (chromatin decompaction), which suggests there is a mechanism for exposing this acidic patch when nucleosome binding is necessary without having to unfold the structure.
The team’s study also revealed that the histones in the columnar structure help to stabilise and mediate it, and this is due to a series of synergistic DNA and histone interactions. Histones are proteins that play an important role in the structural support of chromosomes. Strands of chromatin wrap themselves around histones, allowing the long strands to be more tightly packed and for the chromosome to have a more compact shape. Each histone has a ‘tail’ region which assists in the regulation of chromosomal structure and accessibility. These tails are involved in the histone-mediated interactions in these telomeric chromatin columnar structures, allowing for the necessary destabilisation of the structure when important DNA damage repair proteins need more access to carry out their roles.
Another aspect of the columnar structure that the team discovered are the presence of ‘supergrooves’ along the structure. These ‘supergrooves’ are formed when several major and minor grooves, that span multiple nucleosomes, align. The team speculated that these ‘supergrooves’ provide sites for the capping and compaction of telomeric chromatin.
Finally, the team also noted that because DNA is fully exposed in the columnar structure, as opposed to being buried within like in other zig-zag and solenoid structures, they are therefore more susceptible to damage. However, on the flip side, the exposed DNA is also more accessible to proteins that are important to DNA damage repair.
The future
By understanding the structural organisation and dynamics of telomeric chromatin at the molecular level, it opens new avenues for future studies regarding DNA damage repair proteins and epigenetics – the study of how behaviours and environments cause changes without affecting how genes work. Ultimately, by better understanding our telomeres, we can develop better templates from which to understand ageing and cancer, and perhaps even come up with medical procedures in the future to address ageing concerns and treat cancers more effectively.
Read the paper in Nature here.
Read NTU’s news release here & Straits Times feature here.