Alternative Lengthening of Telomeres

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Alternative Lengthening of Telomeres (also known as "ALT") is a telomerase-independent mechanism by which cancer cells avoid the degradation of telomeres.

Contents

Background

At each end of the chromosomes of most eukaryotic cells, there is a telomere: a region of repetitive nucleotide sequences which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. At each cell division, the telomeres get shorter, eventually preventing further cell division. Healthy adult somatic cells in mammals do not have active telomerase enzymes, so that cancer cells stop proliferating unless they have a mutation which restores the telomeres. Often, this is due to a telomerase enzyme being reactivated, but alternative mechanisms also occur.

Mechanism of recombination-mediated telomere synthesis

Mechanisms of Alternative Lengthening of Telomeres by a recombination based mechanism. (a) Schematic of conservative replication of DNA by break-induced telomere synthesis. (b) Four potential sources of DNA/telomere sequence that can be copied during new telomere synthesis by ALT Mechanisms of Alternative Lengthening of Telomeres.gif
Mechanisms of Alternative Lengthening of Telomeres by a recombination based mechanism. (a) Schematic of conservative replication of DNA by break-induced telomere synthesis. (b) Four potential sources of DNA/telomere sequence that can be copied during new telomere synthesis by ALT

The main alternative lengthening mechanism for telomeres is a type of homologous recombination called Break-induced Telomere Synthesis (or BITS). [1] Normally, homologous recombination allows broken DNA strands to be repaired by lining up with a matching sequence of undamaged DNA, but in BITS, this mechanism is used to extend telomeres. Because telomeres are by nature repetitive, matching sequences are widely available.

In proposed models for how BITS works, the process begins with the resection of a damaged telomere end: one of the strands is cut away to provide a single strand of DNA (the Guanosine-rich strand) that can bind to into a matching (homologous) template, forming a so-called displacement loop (D-loop) (Figure 1a). [2] In ALT, there is evidence that this template consists of: (i) a centromere proximal sequence of the same chromosome (T-loop), (ii) circular extrachromosomal telomeric sequences (C-circles), (iii) homologous chromosomes, or (iv) other chromosomes (Figure 1b). ALT may arise from a combination of some or all of these templates. [3] Importantly, because telomeres are highly repetitive, invasion between or within telomeres is not limited by the requirement for extended homology in homologous recombination. After D-loop formation, DNA polymerase δ extends the invaded G-strand end, copying material beyond the original breakpoint, leading to initiation of lagging strand synthesis of the C-strand, also by DNA polymerase δ. [4]

The second feature of ALT is the production of a non-conservative DNA product at the telomere. At the conclusion of the copying reaction, both strands contain entirely new DNA. This is different from normal ‘semi-conservative’ DNA replication, where one strand is newly synthesized, and the other comes from the original template. In this manner, ALT allows entire telomeric sequences to be copied from one chromosome to another, without affecting the length or integrity of the copied sequence. Recent work suggests that ALT DNA copying (BITS) proceeds via a D-loop migration model, which is supported by the observation of non-conservative rather than semi-conservative products of break-induced replication at ALT telomeres [5] and the D-loop-shaped products observed in two-dimensional gel electrophoresis at sites undergoing BIR. [6]

Related Research Articles

<span class="mw-page-title-main">DNA replication</span> Biological process

In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.

<span class="mw-page-title-main">Reverse transcriptase</span> Enzyme which generates DNA

A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, by retrotransposon mobile genetic elements to proliferate within the host genome, and by eukaryotic cells to extend the telomeres at the ends of their linear chromosomes. Contrary to a widely held belief, the process does not violate the flows of genetic information as described by the classical central dogma, as transfers of information from RNA to DNA are explicitly held possible.

<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">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called non-coding RNAs (ncRNAs). mRNA comprises only 1–3% of total RNA samples. Less than 2% of the human genome can be transcribed into mRNA, while at least 80% of mammalian genomic DNA can be actively transcribed, with the majority of this 80% considered to be ncRNA.

<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

<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. NHEJ is referred to as "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">Hayflick limit</span> Limit to divisions of a normal human cell

The Hayflick limit, or Hayflick phenomenon, is the number of times a normal somatic, differentiated human cell population will divide before cell division stops. However, this limit does not apply to stem cells.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

Subtelomeres are segments of DNA between telomeric caps and chromatin.

Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive genes in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive genes. Mitotic homologous recombination occurs mainly between sister chromatids subsequent to replication. Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous chromatids is only about 1% of that between sister chromatids.

In molecular biology, a displacement loop or D-loop is a DNA structure where the two strands of a double-stranded DNA molecule are separated for a stretch and held apart by a third strand of DNA. An R-loop is similar to a D-loop, but in this case the third strand is RNA rather than DNA. The third strand has a base sequence which is complementary to one of the main strands and pairs with it, thus displacing the other complementary main strand in the region. Within that region the structure is thus a form of triple-stranded DNA. A diagram in the paper introducing the term illustrated the D-loop with a shape resembling a capital "D", where the displaced strand formed the loop of the "D".

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">FANCM</span> Mammalian protein found in Homo sapiens

Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ is the use of microhomologous sequences during the alignment of broken ends before joining, thereby resulting in deletions flanking the original break. MMEJ is frequently associated with chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements.

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.

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.

<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.

Jan Karlseder is an Austrian molecular biologist, 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.

References

  1. 1 2 O'Rourke, JJ; Bythell-Douglas, R; Dunn, EA; Deans, AJ (December 2019). "ALT control, delete: FANCM as an anti-cancer target in Alternative Lengthening of Telomeres". Nucleus (Austin, Tex.). 10 (1): 221–230. doi:10.1080/19491034.2019.1685246. PMC   6949022 . PMID   31663812. CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  2. ↑ Zhang, JM; Yadav, T; Ouyang, J; Lan, L; Zou, L (22 January 2019). "Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways". Cell Reports. 26 (4): 955–968.e3. doi:10.1016/j.celrep.2018.12.102. PMC   6366628 . PMID   30673617.
  3. ↑ O’Rourke, Julienne J; Bythell-Douglas, Rohan; Dunn, Elyse A; Deans, Andrew J (1 January 2019). "ALT control, delete: FANCM as an anti-cancer target in Alternative Lengthening of Telomeres". Nucleus. 10 (1): 221–230. doi:10.1080/19491034.2019.1685246. PMC   6949022 . PMID   31663812.
  4. ↑ Donnianni, RA; Zhou, ZX; Lujan, SA; Al-Zain, A; Garcia, V; Glancy, E; Burkholder, AB; Kunkel, TA; Symington, LS (7 November 2019). "DNA Polymerase Delta Synthesizes Both Strands during Break-Induced Replication". Molecular Cell. 76 (3): 371–381.e4. doi:10.1016/j.molcel.2019.07.033. PMC   6862718 . PMID   31495565.
  5. ↑ Min, J; Wright, WE; Shay, JW (15 October 2017). "Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes". Molecular and Cellular Biology. 37 (20). doi:10.1128/MCB.00226-17. PMC   5615184 . PMID   28760773.
  6. ↑ Sneeden, JL; Grossi, SM; Tappin, I; Hurwitz, J; Heyer, WD (May 2013). "Reconstitution of recombination-associated DNA synthesis with human proteins". Nucleic Acids Research. 41 (9): 4913–25. doi:10.1093/nar/gkt192. PMC   3643601 . PMID   23535143.
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