Telomeres and Telomerase: Protecting Chromosomal Integrity

Cellular division is a fundamental process for life, but it presents a challenge. With each replication cycle, a bit of DNA is lost from the ends of chromosomes. This loss threatens the integrity and stability of the entire genome. Telomeres and telomerase are specialized structures and enzymes that work together to safeguard these chromosome ends, ensuring the faithful transmission of genetic information across generations.

The Structure of Telomeres: Repetitive Caps for Chromosomal Stability

Telomeres are specialized nucleoprotein structures that cap the extremities of linear eukaryotic chromosomes. In humans, these caps consist of tandem repeats of the TTAGGG sequence (thousands of times!) on the chromosome's G-rich strand, which overhangs the complementary C-rich strand. This overhang forms a crucial element for telomere function.

Human chromosomes (grey) capped by telomeres (white)

Associated with the telomeric DNA is a complex of proteins known as shelterin. Shelterin guards the telomere, preventing it from being recognized by the cell as a damaged DNA end. This is critical, as the DNA damage response machinery could initiate inappropriate repair processes, potentially fusing chromosomes or triggering cell death.

Telomerase: The Enzyme that Rebuilds Telomeric Repeats

Telomerase is a specialized reverse transcriptase enzyme with a remarkable ability to synthesize telomeric DNA. It utilizes an internal RNA template within its structure to elongate the G-rich overhang at the chromosome terminus. This counteracts the natural shortening of telomeres that occurs during cell division due to the end replication problem (DNA polymerase's inability to fully replicate the lagging strand).

Synthesis of chromosome ends by telomerase

Telomerase activity is tightly regulated and is generally low in most somatic cells. However, it is highly active in stem cells and germline cells, ensuring the maintenance of telomere length in these populations critical for long-term tissue renewal and reproduction.

The Significance of Telomeres and Telomerase in Aging and Cancer

Telomere shortening is considered a hallmark of cellular aging. As cells divide repeatedly, telomeres become progressively shorter. When telomeres reach a critically short length, they can no longer effectively shield chromosomes, leading to chromosomal instability. This instability can trigger cellular senescence (permanent cell cycle arrest) or apoptosis .

The link between telomere shortening and aging is supported by studies demonstrating a strong correlation between shorter telomeres and increased risk of age-related diseases. However, the cause-and-effect relationship is still under investigation.

Telomerase dysfunction is another key player in aging and cancer. Uncontrolled cell proliferation is a defining characteristic of cancer. Cancer cells often exhibit reactivation of telomerase, allowing them to maintain telomere length and bypass replicative senescence, thereby fueling their uncontrolled growth.

Schematic of telomere shortening contributing to age-related cardiac disease. Telomeres shorten with cell division and aging is associated with reduced telomere length. Mitochondria are particularly vulnerable. Critically short telomeres lead to mitochondrial DNA damage, ultimately disrupting mitochondrial function and inducing senescence. Through secretion of senescence-associated secretory phenotype (SASP) factors, senescent cells induce fibrosis and promote cardiomyocyte loss, eventually leading to cardiac dysfunction. Exercise has been shown to protect the heart against cardiac aging and cardiac dysfunction by modulating each step in this sequence.

Telomere and telomerase play important roles in cellular biology and tumorigenesis. Telomeres are specialized structures that are located at the ends of chromosomes. They are composed of DNA repeating sequences (TTAGGG). Shelterin complexes are specific proteins known to protect chromosomes and regulate telomere length. Telomerase is a reverse transcriptase that synthesizes telomeric DNA sequences to maintain telomere length. Telomerase comprises two major components: the telomeric RNA component (TERC) and the telomerase reverse transcriptase (TERT). Other proteins, such as dyskerin, are also found in a complex with TERC. Telomeres shorten with each round of cell division and this mechanism limits the proliferation of cells to a finite number of cell divisions. Unlike normal cells, cancer cells are characterized by high telomerase activity, which could be achieved via mechanisms including TERT genetic alterations, TERT epigenetic change, or structural variants. TERT promoter mutations are the most common alternation and have been reported in several malignancies such as melanoma, genitourinary cancers, CNS tumors, hepatocellular carcinoma, thyroid cancers, sarcomas, and HNCs. In HNCs, the frequency of TERT promoter mutations is high (11.9–64.7% based on different studies).

Understanding the complex interplay between telomeres, telomerase, and cellular processes is crucial for advancing our knowledge of aging and cancer. Research in this field holds immense promise for the development of novel therapeutic strategies aimed at targeting telomere maintenance mechanisms to combat age-related diseases and malignancies.

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Telomeres and Telomerase: Protecting Chromosomal Integrity
Gen store May 21, 2024
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