Name: telomeres, telomerase, and tumor control
Uploaded: 2021-04-07T12:12:01.000Z
Duration: 2 min 15 s
Channel: JoVE

Most animal cells divide a finite number of times before they stop and undergo permanent cell cycle arrest.
In a mitogenic medium, for example, human fibroblast cells divide about 25-50 times. As a cell approaches this finite number of divisions, the rate of cell division slows down and finally halts with cells entering a permanent non-dividing state. This phenomenon is called replicative cell senescence.
Replicative cell senescence is a result of changes in the structure of telomeres. Telomeres are located at the ends of the chromosomes and consist of long repetitive DNA sequences and protein complexes.
In the absence of telomeres, chromosome ends could be recognized as double-strand breaks. These ends could fuse to one another forming abnormal structures like a ring chromosome. The telomeres act as caps, protecting the ends of the chromosomes from degradation by nucleases and preventing the aberrant fusion of chromosome ends to one another.
Shelterin is a telomere-associated protein complex that protects the chromosome ends.
Shelterin helps DNA ends form a lariat-like structure called a telomerase-loop, or T-loop. This T-loop masks the DNA ends, preventing degradation.
During cell division, telomeres are shortened by 25-200 bases due to the inability of the polymerase to completely replicate DNA ends. As the length of telomeres becomes shorter, the shelterin components are displaced from the telomere region. Shrinking of the telomere eventually destabilizes the t-loop conformation.
The change in the T-loop structure leaves the chromosome ends exposed, which are sensed as DNA damage by the DNA damage response pathway.
The persistent DNA damage response that ensues induces replicative cell senescence which helps limit genomic instability and malignant transformation.

replicative cell senescence

Replicative Cell Senescence

Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism&#39;s lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere &#8212; short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase &#8212; an enzyme that adds the telomeric repeat sequence and enables repetitive cell division; however, in adults, telomerase is active only in the cells that need to divide regularly.
Because telomerase is inactive in most human somatic cells, the length of the telomere decreases with every cell division. After a critical length, telomere shortening leads to permanent cell cycle arrest. This mechanism is assumed to protect against cancer development by limiting the abnormal proliferation of tumors; however, a rare mutation can activate telomerase, which reconstructs the telomere region, allowing the cells to proliferate. Thus, telomerase is a perfect target for specific anticancer therapy, as most cancer cells express telomerase while normal cells do not.
The relation between telomere length and tumor formation has been experimentally verified using oncogenic mice. Oncogenic mice are mouse models that have cancer-causing genes. When such oncogenic mice are crossed with telomerase-deficient mice that lack telomerase activity, the resultant progeny mice express shorter telomeres than the oncogenic parent. These progeny mice, when interbred, generate successive generations that have progressively shorter telomeres. The frequency of tumor formation is studied by treating the progeny mice with carcinogens at every generation. As per the results, the late generation mice with shorter telomeres exhibit a reduced frequency of tumor formation compared to the early generation mice that maintain longer telomeres. This proves that limiting the replicative capacity of cells suppresses tumor formation.

Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism&#39;s lifespan while ...

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JoVE Core

Molecular Biology

Unit 2

Cell Proliferation

KEY TERMS AND CONCEPTS

telomeres, telomerase, and tumor control

Telomeres and telomerase help control how many times a cell can divide. Telomeres are short, repetitive DNA sequences at the ends of chromosomes. They are covered by proteins that form a protective cap. In many human body cells, this cap gets a little shorter after each round of cell division.

This shortening is part of replicative senescence, the point at which a cell stops dividing permanently. Embryonic stem cells make telomerase, an enzyme that adds telomeric repeats and supports repeated cell division. In adults, telomerase stays active only in cells that need to divide regularly. In most somatic cells, telomerase is inactive, so telomeres keep shrinking until they reach a critical length.

When telomeres become too short, the cell cycle stops. This helps limit excessive cell growth and is thought to protect against cancer. A rare mutation can switch telomerase back on. That allows the telomere region to be rebuilt and lets cells keep proliferating. Because most cancer cells express telomerase, the enzyme is a useful target for specific anticancer therapy.

The link between telomere length and tumor formation has been tested in oncogenic mice, which are mouse models carrying cancer-causing genes. Scientists crossed these mice with telomerase-deficient mice, which lack telomerase activity. The offspring had shorter telomeres than the oncogenic parent. When these mice were bred for successive generations, the telomeres became even shorter each time.

Researchers then treated each generation with carcinogens and measured tumor formation. Late-generation mice with shorter telomeres formed tumors less often than early-generation mice with longer telomeres. These results show that limiting the replicative capacity of cells can reduce tumor formation.

Telomeres, Telomerase, and Tumor Control

what is the cell cycle?

Cell Growth and Division in the Cell Cycle

The cell cycle is the process that cells use to grow and divide. It helps living things make new cells for growth and repair. In many cases, it is also the way single cells reproduce. The cycle has two main parts: interphase and cell division. During interphase, the cell grows and prepares for division. During cell division, one cell splits into new cells. This sequence keeps cells in a repeating pattern of growth, copying, and splitting.

interphase

Interphase in the Cell Cycle

Interphase is the part of the cell cycle when a cell grows and prepares to divide. It is a major stage in the life of a cell, and it includes the phases G1, S, and G2. During G1, the cell grows and carries out its normal functions. In the S phase, the cell copies its DNA. During G2, the cell continues to grow and gets ready for mitosis, the stage when the cell divides. Interphase takes up most of the cell cycle. It gives the cell time to build materials, make a copy of its genetic...

the cell cycle control system

How Cell Division Is Controlled

The cell cycle is the organized process that controls cell division. It helps one cell divide into two daughter cells with chromosomes that match the parent cell. This process is essential for growth from a single-cell zygote and for tissue renewal in adult multicellular eukaryotes. Cell division also supports repair and replacement in the body. In bone marrow, stem cells divide to make new blood cells. When cell division happens without control, it can lead to cancer and many genetic diseases.

positive regulator molecules

Cyclins and Cdks in Cell Cycle Control

Cyclins and cyclin-dependent kinases help control how cells move through the cell cycle. These positive regulator molecules keep mitotic cell division on schedule so daughter cells can match the parent cell. When this control fails, errors in DNA replication or in the distribution of genetic material can create mutant cells that pass those changes to every new cell they form. Cell cycle checkpoints limit the spread of these abnormal cells. A checkpoint is a control point at a specific stage of...

inhibition of cdk activity

Cdk4/6 Blockers and Cell Cycle Control

Cdk4/6 blockers help control the cell cycle by stopping the signals that push cells from G1 into S phase. Cdks, or cyclin-dependent kinases, must bind cyclins to become active, and cyclin D often pairs with Cdk4/6 to form this active complex. The cyclin D-Cdk4/6 complex then phosphorylates the retinoblastoma protein, or Rb, which normally acts as a tumor suppressor. When Rb is inactivated, cells can move into the next stage of division. In normal cells, Cdk activity is carefully regulated so...

s-cdk initiates dna replication

Cdk Control of DNA Replication Timing

Cdk control of DNA replication timing helps cells copy DNA once each cycle. The cell cycle has four main stages: G1, S, G2, and M. In G1, the cell grows. In S phase, it copies its DNA. In G2, it prepares to divide. In M phase, mitosis divides the cell content into two daughter cells. In eukaryotes, DNA replication starts at many sites on the chromosomes called origins of replication. These origins switch between two states during the cell cycle. In G1, a multiprotein pre-replicative complex,...

m-cdk drives transition into mitosis

Cell Cycle Kinases Trigger Entry into Mitosis

Cell cycle kinases help control the move from G2 into M phase. Checkpoints act as safeguards and gatekeepers, so the cell cycle can continue in good conditions and slow down or stop when problems appear. This regulation is called the cell cycle control system. Cyclin-dependent kinases, or Cdks, work with cyclins to manage cell cycle transitions. A key example is M-Cdk, which is made of Cdk1 bound to M cyclin. M-Cdk helps drive the shift from G2 to M phase by preparing the cell for mitosis. M...

mitogens and the cell cycle

EGF Signaling and Cancer Cell Growth

Epidermal growth factor, or EGF, is a mitogen that helps control cell division. Its receptor, EGFR, sits in the cell membrane and sends a growth signal when EGF binds to it. EGFR is part of the ErbB family of tyrosine kinase receptors, and this signaling helps decide whether a cell will keep proliferating. In healthy tissue, the number of EGFR molecules on the cell surface is tightly regulated. This balance helps cell division match the tissue’s needs. In cancer cells, however, EGFR is often...

Telomeres and telomerase help control how many times a cell can divide. Telomeres are short, repetitive DNA sequences at the ends of chromosomes. They are covered by proteins that form a protective cap. In many human body cells, this cap gets a little shorter after each round of cell division. This shortening is part of replicative senescence, the point at which a cell stops dividing permanently. Embryonic stem cells make telomerase, an enzyme that adds telomeric repeats and supports repeated...

abnormal proliferation

Ras and MYC in Uncontrolled Cell Growth

Ras and MYC can drive abnormal cell proliferation, which is uncontrolled cell growth. Under normal conditions, most adult cells stay non-proliferative unless they receive internal or external signals to replace lost cells. In abnormal proliferation, cell division continues even after those signals stop. This persistent growth can lead to tumors. The tumor forms from damaged cells that keep copying themselves. Those cells pass the damage to daughter cells and to later generations of daughter...

cells coordinate growth and proliferation

cells-coordinate-growth-and-proliferation

Cell Size Control in Growth and Muscle

Cell size control helps cells keep their shape, function, and fitness. Many dividing cells grow and then double their mass before they divide. This coordination depends on checkpoints between cell cycle phases, which help the cell stay in balance. When checkpoint control fails, cells may grow without proper control. That loss of coordination can lead to uncontrolled growth and reduced cellular function. In adult tissues, non-dividing cells also adjust size based on metabolic state. Adult...

key terms and concepts

Explore how telomeres and telomerase limit cell division, trigger senescence, and help reduce tumor formation in a high school-friendly biology lesson.

Telomeres, Telomerase, and Tumor Control | JoVE K12

molecular biology

JoVE Core Molecular Biology showcases the molecular processes of the cell through clear and concise animated video lessons. Additionally, in scientist-in-action videos, these concepts' application is demonstrated through real experiments in modern laboratories.

Telomeres, Telomerase, and Tumor Control

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