ALT Associated Mutations in Histone H3, ATRX and DAXX

Print   

11 Apr 2018

Disclaimer:
This essay has been written and submitted by students and is not an example of our work. Please click this link to view samples of our professional work witten by our professional essay writers. Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of EssayCompany.

Besides the contribution of DNA sequence and the state of shelterin binding in telomeric recombination and ALT activity, telomere architecture, and specially histone modifications, are responsible for some phenotypic characteristics of ALT. Recent studies of ALT tumors correlate telomere maintenance mechanism of ALT with activity of the complex ATRX/DAXX.

ATRX and DAXX form a chromatin remodeling complex that moderates chromatin changes. ATRX is responsible for encoding a member of the switch/sucrose non-fermentable (SWI/SNF) family ATP-dependent helicases that have chromatin-remodeling activity namely α-thalassemia mental retardation X-linked protein. DAXX encodes another component of ATRX that is a binding partner death-associated protein 6. ATRX/DAXX complex is needed for chromatin deposition of a histone associated with transcriptionally active open chromatin namely H3.3. It has been reported that the inhibition of this complex suppresses the recombinogenic nature of repetitive telomeric DNA, resulting in loss of hetrochromatic marks. Limitation of expression or loss of the complex ATRX/DAXX show to limit the H3.3 incorporation in telomeric chromatin with a positive effect in telomere recombination. The recruitment of such proteins in detriment of others may affect the construction of ALT telomeres. An example of that are the mutations in H3F3A, the encoding gene of H3.3 that has demonstrated alterations in histone incorporation in the genome with alterations at chromatin remodeling and gene expression.

Loss of ATRX/DAXX activity can originate altered gene expression that can promote ALT activity. This complex has been related with ALT, being associated or not with p53, and the majority of cancers with prevalence of ALT have ATRX mutations. The first correlation between ALT and epigenetic and chromatin dysfunction was found in PanNET and GBM tumors. In these tumors there were observed remains of ALT-associated PML bodies (APBs) and loss of the ATRX (and often) DAXX expression.

It has been described a linkage between ATRX and DNA methylation, chromatin conformation, replication and transcriptional repression, particularly in tandem repeated sections. Loss of ATRX affect telomeres very similarly to ALT, and possibly contributes to ALT activation. The majority of ALT cells exhibit deregulated ATRX expression, however, the sequence is present in the genome, suggesting a role of ATRX protein in ALT suppression, after specific changes in protein maturation.

In addition to ATRX, DAXX and p53 mutations, some tumors exhibit heterozygous mutations in the histone H3.3 gene, H3F3A. It is suggest that these alterations facilitate the activation of TMM by ALT mechanism through the epigenetic changes in the telomeric chromatin. However, some ALT tumors have functional histone H3, ATRX and DAXX expression, which indicates that other fails may contribute to the expression of some ALT hallmarks.

Cells with different TMM have significant differences in telomeric chromatin construction; in ALT cells it is possible to observe more compact telomeric chromatin, relatively with telomerase-dependent cells, that is consistent with most interactions between telomeres observed in these cells allowing HR-dependent telomere maintenance and promoting telomere transcription.

In the majority of tumors with ATRX, DAXX or H3F3A mutations it is also observed p53 mutation, which is indicative of a possible interaction between the mutations.

Non-determined telomere maintenance mechanism

Telomere maintenance mechanism in tumor cells are usually classified in two groups: telomerase-dependent TMM or ALT-dependent TMM. However, this classification is not consensual and there are some studies that identified some groups of tumors with characteristics of both mechanisms or neither.

There are some evidences that ALT pathway may be activated when there is a loss or inhibition of telomerase function. According to the results obtained by Chen et al. ALT telomere elongation is present following telomerase inhibition. In a similar manner, in a study with ALT active cells, the fusion with normal somatic cells or telomerase-positive cancer cells leaded to ALT activity suppression. Unlike to the expected, in a research in which there were used keratinocytes, normal human cells showed the presence of ALT pathway active, but repression of this mechanism in cells telomerase-immortalized. The cells were able to maintain telomeres by both ALT and telomerase and when there is dominance of one mechanism there is competition and further elongation of telomeres. In the same way it has been documented in a research of human sarcomas that the two mechanisms were not mutually exclusive in some tumors being observed in the same tumor some cells having ALT-associated PML bodies, characteristic of ALT, and other expressing telomerase.

The immortalization of cells is considered a general feature of cancer, however, in some conditions the acquirement of limitless growth through the activation of the telomere maintenance mechanisms is not required. Some tumors have neither evidences of the presence of telomerase activity nor ALT. There are some hypothesis to justify that specific condition, that are the fact of the tumor rise in cells that start out with long telomeres; the absence of adverse tumor factors, increasing the cell surviving and the presence of genetic mutations.

ALT-target therapies

At this time, there are no therapies specifically targeting ALT. In some cancer types, particularly some with difficult prognostic, the frequency of ALT mechanisms has increased and the somatic mutations in the ATRX, DAXX and in the histone variant H3.3 found in some tumors can be used as ALT hallmarks. One possibility to target ALT positive cells is through the development of synthetic lethal approaches to kill ATL cells deficient in ATRX or DAXX producing stress for which the genes will act in a protective function.

There are evidences that ALT-dependent cancers use homologous recombination to maintain their telomere length, and this fault in specific cancers can be a promising target to therapy. An efficient therapeutic targeting of TMM in cancers can include the development of ALT inhibitors, since telomerase inhibitors are not effective for ALT tumors. The recent results obtained by Flynn et al. shows hypersensitivity of ATL positive cells to ATR (a critical regulator of recombination) inhibitors and their application in vitro disturb and selectively kill the ALT positive cells. Despite being necessary further research, the application of ATR inhibitors to ALT-positive cancer cells is a promising discovery to clinical studies.

As previously referred, some tumors exhibit telomerase and ALT activity in the same cell and both mechanisms can co-exist. It has been reported in mouse models experiments that in mosaic tumors their survival was promoted by ALT pathway when telomerase was inhibited. In order to obtain an efficient therapeutic; the tumor cells have to be evaluated in what concern the TMM present and in the case of mosaicism, the tumor may be targeted in each type of cell through combination therapies.

In tumors with a single mechanism of telomere maintenance, the treatment with the corresponding inhibitor may lead to the appearance of drug resistance or can treat just the relevant TMM, can be applied selection pressure and activation of the other TMM. Similarly to the treatment of mosaicism tumors, either use of both telomerase and ALT inhibitors is required.

Final remarks and future perspectives:

The unlimited proliferation capacity is one of the hallmarks of cancer and the activation of telomerase maintenance mechanisms (TMM) is essential in tumorigenesis to perform replicative immortality and replication-induced senescence resultant of telomere shortening. The most common mechanism to extend critically short telomeres is the activation of telomerase, but fewer yet significant numbers of tumors extend their telomeres through alternative recombination-based methods- ALT.

In order to develop anticancer therapies targeting ALT mechanisms of TMM, it is needed to intensify the study and the exploration of these alternative mechanisms. There are a number of issues that must be solved, focusing mostly in the epigenetic mechanisms present in ALT telomeres it is necessary to understand the epigenetic landscape and the correlation of the mutations in ALT tumors. For this purpose, the effect of re-introduction the expression of ATRX and the effect of chromatin disruption in ALT cells are experiments that can be performed. It can be further studied the repetitive structure of ALT telomeres and the behavior of each shelterin protein in these cells, specially the TRF2 that seems to have great influence. Furthermore, the specific characteristics of ALT cells like the function of PML bodies and the dynamics of APB formation can contribute to understand the induction of these alternative mechanisms. Complemented with in vivo trials and the research of pharmacological inhibition of ALT tumors it is possible the development of preclinical and clinical studies to treatments and consequently maximize cancer therapeutic efficacy.

References

1. Blackburn EH, Gall JG. A Tandemly Repeated Sequence at the Termini of the Extrachromosomal Ribosomal RNA gene in Tetrahymena. J Mol Biol. 1978;120:33–53.

2. Cech TR, Brehm SL. Replication of the extrachromosomal ribosomal RNA genes of Tetrahymens thermophila. 1981;9(14):3531–43.

3. Muller HJ. The remaking of chromosomes. Collect Net 8. 1938;182–95.

4. O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Struct Mol Biol. Nature Publishing Group; 2010;11(3):171–81.

5. Meyne J, Ratliff RL, Moyzis RK. Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc Natl Acad Sci U S A. 1989;86(18):7049–53.

6. Wright WE, Tesmer VM, Huffman KE, Levene SD, Shay JW. Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev. 1997;11(21):2801–9.

7. Makarov VL, Hirose Y, Langmore JP. Long G tails at Both Ends of Human Chromosomes Suggest a C Strand Degradation Mechanism for Telomere Shortening. Cell. 1997;88(5):657–66.

8. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. Mammalian Telomeres End in a Large Duplex Loop. Cell. 1999;97:503–14.

9. Giardini MA, Segatto M, Da Silva MS, Nunes VS, Cano MIN. Telomere and telomerase biology. Progress in Molecular Biology and Translational Science. 2014. 1-40 p.

10. De Lange T. T-loops and the origin of telomeres. Nat Rev Mol cell Biol Mol cell Biol. 2004;5:323–9.

11. Williamson JR. 1994_Williamson_G-quartet structures in telomeric DNA. Annu Rev Biophys Biomol Struct. 1994;23:703–30.

12. Pedroso IM, Hayward W, Fletcher TM. The effect of the TRF2 N-terminal and TRFH regions on telomeric G-quadruplex structures. Nucleic Acids Res. 2009;37(5):1541–54.

13. Nandakumar J, Cech TR. Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol. 2013;14:69–82.

14. Aubert G, Lansdorp PM. Telomeres and aging. Physiol Rev. 2008;88(2):557–79.

15. Hayflick L. The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp Cell Res. 1965;37:614–36.

16. Cesare AJ, Reddel RR. Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet. 2010;11(5):319–30.

17. Autexier C, Lue NF. The structure and function of telomerase reverse transcriptase. Annu Rev Biochem. 2006;75:493–517.

18. Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J. 1995;14(17):4240–8.

19. Bryan TM, Englezou A, Dalla-Pozza L, Dunham M a, Reddel RR. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med. 1997;3(11):1271–4.

20. Henson JD, Reddel RR. Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers. FEBS Lett. Federation of European Biochemical Societies; 2010;584(17):3800–11.

21. Shay JW, Wright WE. Role of telomeres and telomerase in cancer. Semin Cancer Biol. 2012;21(6):349–53.

22. Lundblad V, Blackburn EH. An alternative pathway for yeast telomere maintenance rescues est1- senescence. Cell. 1993;73(2):347–60.

23. Hrdlickova R, Nehyba J, Bose HR. Alternatively Spliced Telomerase Reverse Transcriptase Variants Lacking Telomerase Activity Stimulate Cell Proliferation. Mol Cell Biol. 2012;32(21):4283–96.

24. Hanahan D, Weinberg R a. Hallmarks of cancer: The next generation. Cell. Elsevier Inc.; 2011;144(5):646–74.

25. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333(6041):425.

26. O’Sullivan RJ, Almouzni G. Assembly of telomeric chromatin to create ALTernative endings. Cell. Elsevier Ltd; 2014;24(11):675–85.

27. Bechter OE, Shay JW, Wright WE. The frequency of homologous recombination in human ALT cells. Cell Cycle. 2004;3(5):547–9.

28. McEachern MJ, Haber JE. Break-induced replication and recombinational telomere elongation in yeast. Annu Rev Biochem. 2006;75:111–35.

29. Natarajan S, McEachern MJ. Recombinational telomere elongation promoted by DNA circles. Mol Cell Biol. 2002;22(13):4512–21.

30. Nabetani A, Ishikawa F. Alternative lengthening of telomeres pathway: Recombination-mediated telomere maintenance mechanism in human cells. J Biochem. 2011;149(1):5–14.

31. Lu W, Zhang Y, Liu D, Songyang Z, Wan M. Telomeres-structure, function, and regulation. Exp Cell Res. Elsevier; 2013;319(2):133–41.

32. Jacobs JJL. Loss of telomere protection: consequences and opportunities. Front Oncol. 2013;3(April):88.

33. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194–8.

34. Wang RC, Smogorzewska A, De Lange T. Homologous recombination generates t-loop-sized deletions at human telomeres. Cell. 2004;119(3):355–68.

35. Sfeir A, Kabir S, Overbeek M, Celli G, de Lange T. Loss of Rap1 induces telomere recombination in absence of NHEJ or a DNA damage signal. Science (80- ). 2010;327(5973):1657–61.

36. Van Steensel B, Smogorzewska A, De Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998;92(3):401–13.

37. Hockemeyer D, Sfeir AJ, Shay JW, Wright WE, de Lange T. POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J. 2005;24(14):2667–78.

38. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, De T, et al. Loss of ATRX , Genome Instability , and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway. 2012;8(7):12–5.

39. Poulet A, Buisson R, Faivre-Moskalenko C, Koelblen M, Amiard S, Montel F, et al. TRF2 promotes, remodels and protects telomeric Holliday junctions. EMBO J. 2009;28(6):641–51.

40. Conomos D, Pickett HA, Reddel RR. Alternative lengthening of telomeres: remodeling the telomere architecture. Front Oncol. 2013;3(February):1–7.

41. Henson JD, Cao Y, Huschtscha LI, Chang AC, Au AYM, Pickett H a, et al. DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity. Nat Biotechnol. Nature Publishing Group; 2009;27(12):1181–5.

42. Marciniak R a., Cavazos D, Montellano R, Chen Q, Guarente L, Johnson FB. A novel telomere structure in a human alternative lengthening of telomeres cell line. Cancer Res. 2005;65(7):2730–7.

43. Gocha ARS, Harris J, Groden J. Alternative mechanisms of telomere lengthening: Permissive mutations, DNA repair proteins and tumorigenic progression. Mutat Res - Fundam Mol Mech Mutagen. Elsevier B.V.; 2013;743-744:142–50.

44. Sengupta S, Harris CC. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol. 2005;6(1):44–55.

45. Preto A, Singhrao SK, Haughton MF, Kipling D, Wynford-Thomas D, Jones CJ. Telomere erosion triggers growth arrest but not cell death in human cancer cells retaining wild-type p53: implications for antitelomerase therapy. Oncogene. 2004;23(23):4136–45.

46. Olivier M, Hollstein M, Hainaut P. TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Cold Spring Harb Prospect Biol. 2010;2(1):17.

47. Goldberg AD, Banaszynski L a., Noh KM, Lewis PW, Elsaesser SJ, Stadler S, et al. Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions. Cell. Elsevier Ltd; 2010;140(5):678–91.

48. Lewis PW, Elsaesser SJ, Noh K-M, Stadler SC, Allis CD. Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci U S A. 2010;107(32):14075–80.

49. Episkopou H, Draskovic I, Van Beneden A, Tilman G, Mattiussi M, Gobin M, et al. Alternative Lengthening of Telomeres is characterized by reduced compaction of telomeric chromatin. Nucleic Acids Res. 2014;42(7):4391–405.

50. Schwartzentruber J, Korshunov A, Liu X-Y, Jones DTW, Pfaff E, Jacob K, et al. Corrigendum: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;484(7392):130–130.

51. Chen W, Xiao BK, Liu JP, Chen SM, Tao ZZ. Alternative lengthening of telomeres in hTERT-inhibited laryngeal cancer cells. Cancer Sci. 2010;101(8):1769–76.

52. Perrem K, Colgin LM, Neumann a a, Yeager TR, Reddel RR. Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 cells. Mol Cell Biol. 2001;21(12):3862–75.

53. Bojovic B, Booth RE, Jin Y, Zhou X, Crowe DL. Alternative lengthening of telomeres in cancer stem cells in vivo. Oncogene. Nature Publishing Group; 2014;(April 2013):1–10.

54. Gocha ARS, Nuovo G, Iwenofu OH, Groden J. Human sarcomas are mosaic for telomerase-dependent and telomerase- independent telomere maintenance mechanisms: Implications for telomere-based therapies. Am J Pathol. American Society for Investigative Pathology; 2013;182(1):41–8.

55. Dunham M a, Neumann A a, Fasching CL, Reddel RR. Telomere maintenance by recombination in human cells. Nat Genet. 2000;26(4):447–50.

56. Reddel RR. Telomere Maintenance Mechanisms in Cancer: Clinical Implications Centromere Growth Arrest. 2014;6361–74.

57. Flynn RL, Cox K, Jeitany M, Wakimoto H, Bryll A, Ganem N, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science (80- ). 2015;347(6219):273–7.

58. Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, et al. Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer. Cell. Elsevier Inc.; 2012;148(4):651–63.



rev

Our Service Portfolio

jb

Want To Place An Order Quickly?

Then shoot us a message on Whatsapp, WeChat or Gmail. We are available 24/7 to assist you.

whatsapp

Do not panic, you are at the right place

jb

Visit Our essay writting help page to get all the details and guidence on availing our assiatance service.

Get 20% Discount, Now
£19 £14/ Per Page
14 days delivery time

Our writting assistance service is undoubtedly one of the most affordable writting assistance services and we have highly qualified professionls to help you with your work. So what are you waiting for, click below to order now.

Get An Instant Quote

ORDER TODAY!

Our experts are ready to assist you, call us to get a free quote or order now to get succeed in your academics writing.

Get a Free Quote Order Now