Telomeres in the cell cycle

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Telomeres, the caps on the ends of eukaryotic chromosomes, play critical roles in cellular aging and cancer. An important facet to how telomeres function in these roles is their involvement in cell cycle regulation.

Contents

Eukaryotic cells

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. [1] This problem makes eukaryotic cells unable to copy the last few bases on the 3' end of the template DNA strand, leading to chromosome—and, therefore, telomere—shortening every S phase. [2] Measurements of telomere lengths across cell types at various ages suggest that this gradual chromosome shortening results in a gradual reduction in telomere length at a rate of approximately 25 nucleotides per year. [3]

Cell cycle enablers and regulators

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). [4] [5] Without a protective cap, chromosome ends would appear identical to intrachromosomal DSBs. These DSBs activate a DNA damage response pathway that halts the cell cycle until the breaks are repaired. This checkpoint pathway is initiated in S. cerevisiae by recruitment of protein kinases Mec1 and Tel1 and in mammals by recruitment of protein kinases ATR and ATM. [6] Regarding DSB repair, eukaryotes generally use two strategies: non-homologous end joining (NHEJ), which involves rapid reattachment of the broken ends; and homologous recombination (HR), which involves the use of a homologous DNA sequence to repair the break. Because HR requires a homologous sequence, its use is restricted to S/G2 phase. [7] (Interestingly, as with many other aspects of the cell cycle, [8] cyclin-dependent kinases are responsible for downregulating NHEJ during S/G2 phase to ensure use of the more accurate HR. [9] ) As shown in Figure 1A, telomere-shelterin complexes contain motifs that inhibit the DNA damage checkpoint, NHEJ, and HR.

Initial work on the role of telomere-bound protein complexes in S. cerevisiae elucidated the mechanism by which these complexes prevent checkpoint activation and DSB repair of chromosome ends. The two major protein complexes that bind to telomeric DNA in S. cerevisiae are:[ citation needed ]

The CST complex and Rif1 prevent Mec1 recruitment, thereby preventing checkpoint activation. [5] [10] Meanwhile, Rif2 and Rap1 inhibit NHEJ: knocking out Rif2 or Rap1 results in longer telomeres as measured by PCR, indicating that NHEJ occurred. [11] These knockout strains (unlike strains lacking functional CST or Rif1) continue to cycle, further suggesting that Rif2 and Rap1 are not involved in inhibiting checkpoint activation. [12]

Analogously, proteins that bind to human telomeres as part of the shelterin complex enable cell cycle progress and prevent erroneous DSB repair. POT1 protein binds to ssDNA, prevents checkpoint activation through inhibiting ATR recruitment, and prevents HR; [13] [14] RAP1, a GTPase, binds to dsDNA and prevents HR; [15] and TRF2 protein (also known as TERF2) binds to dsDNA, prevents checkpoint activation through inhibiting ATM recruitment, and prevents NHEJ. [16] [17] TRF2 is unique among these proteins in its role in the formation and maintenance of T-loops: lariat structures formed by the folding of the ssDNA overhang back onto the dsDNA. T-loops may further inhibit the binding of checkpoint activation proteins. [18]

Figure 1. (A) Telomere-bound proteins involved in preventing the activation of the DNA damage response checkpoint and of DSB repair mechanisms in S. cerevisiae (top) and in humans (bottom). (B) Overview of the normal function of telomere-shelterin complexes and the pathways activated by telomere shortening. Shelterin-telomere complexes.png
Figure 1.(A) Telomere-bound proteins involved in preventing the activation of the DNA damage response checkpoint and of DSB repair mechanisms in S. cerevisiae (top) and in humans (bottom). (B) Overview of the normal function of telomere-shelterin complexes and the pathways activated by telomere shortening.

As telomeres shorten as a natural consequence of repeated cell division or due to other factors, such as oxidative stress, [19] shelterin proteins lose the ability to bind to telomeric DNA. When telomeres reach a critically short length, sufficient shelterin proteins to inhibit checkpoint activation are not available, although NHEJ and HR generally remain inhibited at this point. [5] This loss of inhibition is one reason why telomere shortening causes senescence (Figure 1B).

Telomeres and cell cycle deregulation

Almost all cancer cells have shortened telomeres. [20] This may seem counter-intuitive, as short telomeres should activate the ATR/ATM DNA damage checkpoint and thereby prevent division. Resolving the question of why cancer cells have short telomeres led to the development of a two-stage model for how cancer cells subvert telomeric regulation of the cell cycle. First, the DNA damage checkpoint must be inactivated to allow cells to continue dividing even when telomeres pass the critical length threshold. This requirement follows not only from the discussion above but also from in vivo evidence showing the function of this checkpoint in precancerous lesions and its dysfunction in late-stage tumors. [21] Second, to survive after disabling the DNA damage checkpoint, precancerous cells must activate mechanisms to extend their telomeres. [22] [23] As a result of the continued division past the point of normal senescence, the telomeres of these cells become too short to prevent NHEJ(Non Homologous End Joining) and HR(Homologous Recombination) of chromosome ends, causing a state known as crisis. [24] 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. [23] To survive and replicate, precancerous cells must stabilize their telomere lengths. This occurs through telomerase activation or the activation of a telomere-recombination pathway (i.e., the ALT pathway). [22] [25] 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.[ citation needed ]

Since the late 1990s, researchers have proposed using telomerase inhibitors as cancer treatments. [26] [27] [28] While such inhibitors have been seriously considered for cancer therapy since the late 2000s, they are not commonly used. [29] Two concerns with applying telomerase inhibitors in cancer treatment are that effective treatment requires continuous, long-term drug application and that off-target effects are common. [30] For example, the telomerase inhibitor imetelstat, first proposed in 2003, [31] [32] has been held up in clinical trials due to hematological toxicity. [30] Despite these concerns, the development of telomerase-based cancer treatments remains an active research area.[ citation needed ]

Cell cycle timing of telomere elongation

Although telomerase activation does not occur during the cell cycle of normal somatic human cells, the association between telomere elongation (especially elongation by telomerase) and tumor development emphasizes the importance of understanding when such elongation can occur during the cell cycle. Work with S. cerevisiae has identified telomerase activity as restricted to late S phase. [33] [34] Researchers generated S. cerevisiae strains with galactose-inducible shortened telomeres. [33] They then used α factor to block cells with induced short telomeres in late G1 phase and measured the change in telomere length when the cells were released under a variety of conditions. They found that when the cells were released and concurrently treated with nocodazole, a G2/M phase cell cycle inhibitor, telomere length increased for the first few hours and then remained constant. In comparison, when cells were released and allowed to cycle, telomere length increased linearly with time. [34] These data suggest that telomere elongation occurs only in S phase. Additional experiments with greater time resolution support this hypothesis and narrow the timeframe to late S phase. Researchers tied telomere elongation in these experiments to telomerase activity by observing that in an S. cerevisiae strain with a dysfunctional ALT pathway telomere elongation still occurs. [34]

Related Research Articles

<span class="mw-page-title-main">Cell division</span> Process by which living cells divide

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

<span class="mw-page-title-main">Telomere</span> Region of repetitive nucleotide sequences on chromosomes

A telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Telomeres 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.

<span class="mw-page-title-main">Telomerase</span> Telomere-restoring protein active in the most rapidly dividing cells

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

<span class="mw-page-title-main">Non-homologous end joining</span> Pathway that repairs double-strand breaks in DNA

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.

<span class="mw-page-title-main">Heterogeneous ribonucleoprotein particle</span>

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the proteins bound to a pre-mRNA molecule serves as a signal that the pre-mRNA is not yet fully processed and therefore not ready for export to the cytoplasm. Since most mature RNA is exported from the nucleus relatively quickly, most RNA-binding protein in the nucleus exist as heterogeneous ribonucleoprotein particles. After splicing has occurred, the proteins remain bound to spliced introns and target them for degradation.

Signal interfering DNA (siDNA) is a class of short modified double stranded DNA molecules, 8–64 base pairs in length. siDNA molecules are capable of inhibiting DNA repair activities by interfering with multiple repair pathways. These molecules are known to act by mimicking DNA breaks and interfering with recognition and repair of DNA damage induced on chromosomes by irradiation or genotoxic products.

<span class="mw-page-title-main">Telomeric repeat-binding factor 2</span> Protein

Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene. It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange, where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.

<span class="mw-page-title-main">Telomeric repeat-binding factor 1</span> Protein-coding gene in humans

Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the TERF1 gene.

<span class="mw-page-title-main">MDC1</span> Protein-coding gene in the species Homo sapiens

Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1).

<span class="mw-page-title-main">POT1</span> Protein-coding gene in the species Homo sapiens

Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene.

The MRN complex is a protein complex consisting of Mre11, Rad50 and Nbs1. In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-strand DNA breaks prior to repair by homologous recombination or non-homologous end joining. The MRN complex binds avidly to double-strand breaks both in vitro and in vivo and may serve to tether broken ends prior to repair by non-homologous end joining or to initiate DNA end resection prior to repair by homologous recombination. The MRN complex also participates in activating the checkpoint kinase ATM in response to DNA damage. Production of short single-strand oligonucleotides by Mre11 endonuclease activity has been implicated in ATM activation by the MRN complex.

<span class="mw-page-title-main">Meiotic recombination checkpoint</span>

The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.

Telomere-binding proteins function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin.

Shelterin is a protein complex known to protect telomeres in many eukaryotes from DNA repair mechanisms, as well as to regulate telomerase activity. In mammals and other vertebrates, telomeric DNA consists of repeating double-stranded 5'-TTAGGG-3' (G-strand) sequences along with the 3'-AATCCC-5' (C-strand) complement, ending with a 50-400 nucleotide 3' (G-strand) overhang. Much of the final double-stranded portion of the telomere forms a T-loop (Telomere-loop) that is invaded by the 3' (G-strand) overhang to form a small D-loop (Displacement-loop).

<span class="mw-page-title-main">Titia de Lange</span> Dutch geneticist

Titia de Lange is the Director of the Anderson Center for Cancer Research, the Leon Hess professor and the head of Laboratory Cell Biology and Genetics at Rockefeller University.

<span class="mw-page-title-main">Telomeric repeat–containing RNA</span> Long non-coding RNA transcribed from telomeres

Telomeric repeat–containing RNA (TERRA) is a long non-coding RNA transcribed from telomeres - repetitive nucleotide regions found on the ends of chromosomes that function to protect DNA from deterioration or fusion with neighboring chromosomes. TERRA has been shown to be ubiquitously expressed in almost all cell types containing linear chromosomes - including humans, mice, and yeasts. While the exact function of TERRA is still an active area of research, it is generally believed to play a role in regulating telomerase activity as well as maintaining the heterochromatic state at the ends of chromosomes. TERRA interaction with other associated telomeric proteins has also been shown to help regulate telomere integrity in a length-dependent manner.

Cell cycle withdrawal refers to the natural stoppage of cell cycle during cell division. When cells divide, there are many internal or external factors that would lead to a stoppage of division. This stoppage could be permanent or temporary, and could occur in any one of the four cycle phases, depending on the status of cells or the activities they are undergoing. During the process, all cell duplication process, including mitosis, meiosis as well as DNA replication, will be paused. The mechanisms involve the proteins and DNA sequences inside cells.

<span class="mw-page-title-main">DNA end resection</span> Biochemical process

DNA end resection, also called 5′–3′ degradation, is a biochemical process where the blunt end of a section of double-stranded DNA (dsDNA) is modified by cutting away some nucleotides from the 5' end to produce a 3' single-stranded sequence. The presence of a section of single-stranded DNA (ssDNA) allows the broken end of the DNA to line up accurately with a matching sequence, so that it can be accurately repaired.

<span class="mw-page-title-main">Jan Karlseder</span> Austrian molecular biologist

Jan Karlseder an Austrian molecular biologist, is the Chief Science Officer and a Senior Vice President at the Salk Institute for Biological Studies. He is also a professor in the Molecular and Cellular Biology Laboratory, the Director of the Paul F. Glenn Center for Biology of Aging Research and the holder of the Donald and Darlene Shiley Chair at the Salk Institute for Biological Studies.

<span class="mw-page-title-main">Double-strand break repair model</span>

A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).

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