what happens to the telomere dna over the course of multiple cell divisions

by Prof. Kraig Bauch Published 3 years ago Updated 2 years ago 6 min read

The repeats that make up a telomere are eaten away slowly over many division cycles, providing a buffer that protects the internal chromosome regions bearing the genes (at least, for some period of time).

Full Answer

What happens to the telomere when a cell divides?

Each time a cell divides, the telomeres become shorter. Eventually, the telomeres become so short that the cell can no longer divide. Telomere. Along the chromosomes, which are long pieces of DNA...when you look at them as a picture, they look like lines.

Can DNA be damaged by telomeres?

DNA can be damaged from the increased gene vulnerability from shortened telomeres, exposure to elevated levels of reactive oxygen species, the activation of oncogenes (a.k.a. “cancer genes”), and/or cell to cell fusion.

Is Alternative Lengthening of human telomeres a conservative DNA replication process?

Alternative lengthening of human telomeres is a conservative DNA replication process with features of break−induced replication. EMBO Rep.171731–1737. 10.15252/embr.201643169 [PMC free article][PubMed] [CrossRef] [Google Scholar] Sarek G., Kotsantis P., Ruis P., Van Ly D., Margalef P., Borel V., et al. (2019).

What happens to telomeres as cell division happens?

With each cell replication, the telomeres get shorter and shorter until they're so short that your cells can no longer divide. When cells no longer divide, tissues age. However, telomeres can be rebuilt by an enzyme called telomerase to restore cell division.

What happens to telomeres when DNA replicates?

1:162:11Telomere Replication - YouTubeYouTubeStart of suggested clipEnd of suggested clipThe ends of chromosomes contain a G rich series of repeats. Called a telomere telomere aceMoreThe ends of chromosomes contain a G rich series of repeats. Called a telomere telomere ace recognizes the tip of an existing repeat sequence. Using an RNA template within the enzyme telomerase

What happens to telomeres after mitosis?

Telomere Biology and Glioma Telomeres act as a protective cap at the end of chromosomes but are progressively shortened during mitotic divisions.

What is the role of telomeres in DNA replication?

Telomeres are the physical ends of eukaryotic chromosomes. They protect chromosome ends from DNA degradation, recombination, and DNA end fusions, and they are important for nuclear architecture. Telomeres provide a mechanism for their replication by semiconservative DNA replication and length maintenance by telomerase.

Do telomeres get replicated?

Once the lagging strand is elongated by telomerase, DNA polymerase can add the complementary nucleotides to the ends of the chromosomes and the telomeres can finally be replicated.

What is the role of telomeres in the process of cell division?

Their job is to stop the ends of chromosomes from fraying or sticking to each other, much like the plastic tips on the ends of shoelaces. Telomeres also play an important role in making sure our DNA gets copied properly when cells divide.

Why do telomeres shorten during cell division?

Telomeres are subjected to shortening at each cycle of cell division due to incomplete synthesis of the lagging strand during DNA replication owing to the inability of DNA polymerase to completely replicate the ends of chromosome DNA (“end-replication problem”) (Muraki et al., 2012).

What happens to the chromosome when it loses its telomere?

When the telomere becomes too short, the chromosome reaches a 'critical length' and can no longer be replicated. This 'critical length' triggers the cell to die by a process called apoptosis?, also known as programmed cell death.

Why do telomeres shorten during replication?

What is telomerase in DNA replication?

Telomerase is an RNA-dependent DNA polymerase, meaning an enzyme that can make DNA using RNA as a template. How does telomerase work? The enzyme binds to a special RNA molecule that contains a sequence complementary to the telomeric repeat.

How do telomeres solve the end replication problem?

For example, the end replication problem causes a progressive shortening of telomeric DNA at each round of DNA replication, thus telomeres eventually lose their protective capacity. This phenomenon is counteracted by the recruitment and the activation at telomeres of the specialized reverse transcriptase telomerase.

What happens to cells that have shortened telomeres?

Telomere length shortens with age. Progressive shortening of telomeres leads to senescence, apoptosis, or oncogenic transformation of somatic cells, affecting the health and lifespan of an individual. Shorter telomeres have been associated with increased incidence of diseases and poor survival.

Why do telomeres need to be protected from a cell's DNA repair systems?

Telomeres need to be protected from a cell's DNA repair systems because they have single-stranded overhangs, which "look like" damaged DNA. The overhang at the lagging strand end of the chromosome is due to incomplete end replication (see figure above).

Why are telomeres important?

Telomeres act as caps that protect the internal regions of the chromosomes, and they're worn down a small amount in each round of DNA replication. In this article, we'll take a closer look at why telomeres are needed, why they shorten during DNA replication, and how the enzyme telomerase can be used to extend them.

What enzymes can reverse telomere shortening?

Telomerase. Some cells have the ability to reverse telomere shortening by expressing telomerase, an enzyme that extends the telomeres of chromosomes. Telomerase is an RNA-dependent DNA polymerase, meaning an enzyme that can make DNA using RNA as a template.

What is the overhang on a chromosome?

The overhang at the leading strand end of the chromosome is actually generated by enzymes that cut away part of the DNA. In some species (including humans), the single-stranded overhangs bind to complementary repeats in the nearby double-stranded DNA, causing the telomere ends to form protective loops.

What happens to the last strand of RNA in a human cell?

In human cells, the last RNA primer of the lagging strand may be positioned as much as to nucleotides away from the chromosome end. Thus, the single-stranded overhangs produced by incomplete end replication in humans are fairly long, and the chromosome shortens significantly with each round of cell division.

What is the leading strand of DNA?

When DNA is being copied, one of the two new strands of DNA at a replication fork is made continuously and is called the leading strand. The other strand is produced in many small pieces called Okazaki fragments, each of which begins with its own RNA primer, and is known as the lagging strand.

Where are telomere caps located?

Image credit: " Telomere caps ," by U.S. Department of Energy Human Genome Program (public domain). Repetitive regions at the very ends of chromosomes are called telomeres, and they're found in a wide range of eukaryotic species, from human beings to unicellular protists.

What happens if a cell has a short telomere?

This leads to extremely shortened telomeres and increased genomic instability. If the cell continues to survive with extremely short telomeres, then the cell experiences an activation of a telomere maintenance mechanism (either ALT or telomerase). But the risk is that the cell may become cancerous.

What is the function of telomeres?

Telomeres act as the end caps of a chromosome that protect the chromosome’s genetic contents from deteriorating, being lost, or fusing with adjacent chromosomes. The length of a telomere decides how easily chromosome DNA is likely to become corrupted.

What happens when a somatic cell's telomeres become too short?

But when the signals for apoptosis and senescence are absent, the somatic cell continues to divide. This leads to extremely shortened telomeres and increased genomic instability.

What causes telomeres to shorten?

Oxidative Stress & Free Radicals Shorten Telomeres. Well, let’s first consider that one factor that speeds up the shortening of telomeres is free radical exposure. Free radicals can cause damage to cellular DNA, thereby leading to senescence and apoptosis (programmed cell death) in cells.

What enzyme reverses telomere shortening?

Specifically, there is an enzyme called “telomerase” (a.k.a. Telomerase Reverse Transcriptase) that reverses telomere shortening by adding back the TTAGGG genetic sequences to the telomere. But the cell life-extending telomerase enzyme isn’t available ubiquitously.

How does replicative cell senescence occur?

Another way that replicative cell senescence is triggers is through DNA damage. DNA can be damaged from the increased gene vulnerability from shortened telomeres, exposure to elevated levels of reactive oxygen species, the activation of oncogenes (a.k.a. “cancer genes”), and/or cell to cell fusion.

How does stress affect telomeres?

Generally speaking, chronic psychological stress speeds up the rate at which a person’s telomeres are shortened by increasing the level of persistent inflammation in the person and thereby increasing oxidative stress. Oxidative stress damages cells, and increases the demand of cell replication to replace lost cells.

How does telomere shortening affect cell division?

Telomere shortening in humans can induce replicative senescence, which blocks cell division. This mechanism appears to prevent genomic instability and development of cancer in human aged cells by limiting the number of cell divisions. However, shortened telomeres impair immune function that might also increase cancer susceptibility. If telomeres become too short, they have the potential to unfold from their presumed closed structure. The cell may detect this uncapping as DNA damage and then either stop growing, enter cellular old age ( senescence ), or begin programmed cell self-destruction ( apoptosis) depending on the cell's genetic background ( p53 status). Uncapped telomeres also result in chromosomal fusions. Since this damage cannot be repaired in normal somatic cells, the cell may even go into apoptosis. Many aging-related diseases are linked to shortened telomeres. Organs deteriorate as more and more of their cells die off or enter cellular senescence.

Why do telomeres accumulate damage?

Why do telomeres run out?

This is because the telomeres act as a sort of time-delay "fuse", eventually running out after a certain number of cell divisions and resulting in the eventual loss of vital genetic information from the cell's chromosome with future divisions.

What is the end replication problem?

In the early 1970s, Russian theorist Alexei Olovnikov first recognized that chromosomes could not completely replicate their ends; this is called the "end replication problem". Building on this, and to accommodate Leonard Hayflick 's idea of limited somatic cell division, Olovnikov suggested that DNA sequences are lost every time a cell replicates until the loss reaches a critical level, at which point cell division ends.

What is the name of the triple stranded structure that holds DNA onto a region of double strande

This triple-stranded structure is called a displacement loop or D-loop.

How many base pairs are there in a telomere?

Telomere length varies greatly between species, from approximately 300 base pairs in yeast to many kilobases in humans, and usually is composed of arrays of guanine -rich, six- to eight-base-pair-long repeats.

Which cell is telomerase active in?

In most multicellular eukaryotic organisms, telomerase is active only in germ cells, some types of stem cells such as embryonic stem cells, and certain white blood cells.

What are the roles of telomeres in the cell cycle?

An important facet to how telomeres function in these roles is their involvement in cell cycle regulation.

What is the function of telomere shielding complexes?

The telomere-shelterin complexes that cap all eukaryotic chromosomes ensure that healthy cells can progress through the cell cycle by preventing the cellular DNA damage response from identifying chromosome ends as double-stranded breaks (DSBs).

Why do cancer cells have short telomeres?

Thus, cancer cells have short telomeres because they progress through an intermediate stage of telomere shortening—caused by division after DNA damage checkpoint inactivation —before enabling mechanisms for maintaining telomere length. Since the late 1990s, researchers have proposed using telomerase inhibitors as cancer treatments.

Why do shelterin proteins lose their ability to bind to telomeric DNA?

As telomeres shorten, as a natural consequence of cell division or due to other factors, such as oxidative stress , shelterin proteins lose the ability to bind to telomeric DNA.

Why do eukaryotic cells have telomere shortening?

Because eukaryotic chromosomes are linear and because DNA replication by DNA polymerase requires the presence of an RNA primer that is later degraded, eukaryotic cells face the end-replication problem. This problem makes eukaryotic cells unable to copy the last few bases on ...

Why is telomerase inhibitor imetelstat being held up?

For example, the telomerase inhibitor imetelstat, first proposed in 2003, has been held up in clinical trials due to hematological toxicity. Despite these concerns, the development of telomerase-based cancer treatments remains an active research area.

What is the role of DSB in apoptosis?

The application of these DSB (double strand breaks)repair mechanisms to chromosome ends leads to genetic instability, and while this instability can promote carcinogenesis, it induces apoptosis if experienced for too long. To survive and replicate, precancerous cells must stabilize their telomere lengths.

Overview

A telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature most commonly found in eukaryotes. In most, if not all species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double strand break.

Discovery

In the early 1970s, Soviet theorist Alexei Olovnikov first recognized that chromosomes could not completely replicate their ends; this is known as the "end replication problem". Building on this, and accommodating Leonard Hayflick's idea of limited somatic cell division, Olovnikov suggested that DNA sequences are lost every time a cell replicates until the loss reaches a critical level, at which point cell division ends.
In 1975–1977, Elizabeth Blackburn, working as a postdoctoral fellow at Yale University with Joseph G. Gall, discov…

Structure and function

During DNA-replication, DNA polymerase cannot replicate the sequences present at the 3'-ends. This is a consequence of its unidirectional mode of DNA synthesis: it can only attach new nucleotides to an existing 3'-end (that is, synthesis progresses 5'-3') and thus it requires a primer to initiate replication. On the leading strand (oriented 5'-3' within the replication fork), DNA-polymerase continuously replicates from the point of initiation all the way to the strand's end w…

Shortening

Apart from the end replication problem, in vitro studies have shown that telomeres accumulate damage due to oxidative stress and that oxidative stress-mediated DNA damage has a major influence on telomere shortening in vivo. There is a multitude of ways in which oxidative stress, mediated by reactive oxygen species (ROS), can lead to DNA damage; however, it is yet unclear whether the elevated rate in telomeres is brought about by their inherent susceptibility or a diminished activity of DNA repair systems in these regions. Despite widespread agreement of …

Lengthening

The phenomenon of limited cellular division was first observed by Leonard Hayflick, and is now referred to as the Hayflick limit. Significant discoveries were subsequently made by a group of scientists organized at Geron Corporation by Geron's founder Michael D. West, that tied telomere shortening with the Hayflick limit. The cloning of the catalytic component of telomerase enabled experiments to test whether the expression of telomerase at levels sufficient to prevent telom…

Research on disease risk

Telomeres are critical for maintaining genomic integrity and may be factors for age-related diseases. Laboratory studies show that telomere dysfunction or shortening is commonly acquired due process of cellular aging and tumor development.
Observational studies have found shortened telomeres in many types of experimental cancers. In addition, people with cancer have been found to possess shorter leukocyte telomeres than healthy controls. Recent meta-analys…

Measurement

Several techniques are currently employed to assess average telomere length in eukaryotic cells. One method is the Terminal Restriction Fragment (TRF) southern blot. A Real-Time PCR assay for telomere length involves determining the Telomere-to-Single Copy Gene (T/S) ratio, which is demonstrated to be proportional to the average telomere length in a cell.
Tools have also been developed to estimate the length of telomere from whole genome sequencing

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In wildlife

During the last two decades, eco-evolutionary studies have investigated the relevance of life-history traits and environmental conditions on wildlife telomeres. Most of these studies have been conducted in endotherms, i.e. birds and mammals. They have provided evidence for the inheritance of telomere length, however, heritability estimates vary greatly within and among species. Age and telomere length often negatively correlate in vertebrates, but this decline is variable among taxa and linked to the method used for estimating telomere lengt…