LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
O'Driscoll, M; Jeggo, P.A. (2008)
Publisher: Nature Publishing Group
Languages: English
Types: Article
Subjects:

Classified by OpenAIRE into

mesheuropmc: fungi
Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Aschan J. Allogeneic haematopoietic stem cell transplantation: current status and future outlook. Br Med Bull. 2006 January 1, 2006;77-78(1):23-36.
    • 2. Gennery A, Slatter M, Bhattacharya A, Jeggo P, Abinun M, Flood T, et al. Bone marrow transplantation for Nijmegan breakage syndrome. J Pediatr Hematol Oncol. 2005;27(4):239.
    • 3. Resnick IB, Shapira MY, Slavin S. Nonmyeloablative stem cell transplantation and cell therapy for malignant and non-malignant diseases. Transplant Immunology. 2005;14(3-4):207-19.
    • 4. O'Driscoll M, Gennery AR, Seidel J, Concannon P, Jeggo PA. An overview of three disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome. DNA Repair. 2004;3:1227-35.
    • 5. Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche M-C, Sanal O, et al. Cernunnos, a Novel Nonhomologous End-Joining Factor, Is Mutated in Human Immunodeficiency with Microcephaly. Cell. 2006;124(2):287-99.
    • 6. O'Driscoll M, Cerosaletti KM, Girard P-M, Dai Y, Stumm M, Kysela B, et al. DNA Ligase IV mutations identified in patients exhibiting development delay and immunodeficiency. Molecular Cell. 2001;8(6):1175-85.
    • 7. Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell. 2001;105(2):177-86.
    • 8. Ahnesorg P, Smith P, Jackson SP. XLF Interacts with the XRCC4-DNA Ligase IV Complex to Promote DNA Nonhomologous End-Joining. Cell. 2006;124(2):301-13.
    • 9. O'Marcaigh A, DeSantes K, Hu D, Pabst H, Horn B, Li L, et al. Bone marrow transplantation for T-B- severe combined immunodeficiency disease in Athabascan-speaking native Americans. Bone Marrow Transplantation. 2001;27(7):703-9.
    • 10. Gruhn B, Seidel J, Zintl F, Varon R, Tonnies H, Neitzel H, et al. Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure. Orphanet Journal of Rare Diseases. 2007;2(1):5.
    • 11. Kobayashi N, Agematsu K, Sugita K, Sako M, Nonoyama S, Yachie A, et al. Novel Artemis gene mutations of radiosensitive severe combined immunodeficiency in Japanese families. Hum Genet. 2003;112(4):348-52.
    • 12. Buckley RH. Molecular Defects in Human Severe Combined Immunodeficiency and Approaches to Immune Reconstitution. Annual Review of Immunology. 2004;22(1):625-55.
    • 13. Deeg HJ, Leisenring W, Storb R, Nims J, Flowers MED, Witherspoon RP, et al. Long-Term Outcome After Marrow Transplantation for Severe Aplastic Anemia. Blood. 1998;91(10):3637-45.
    • 14. Duncan N, Craddock C. Optimizing the use of cyclosporin in allogeneic stem cell transplantation. Bone Marrow Transplant. 2006;38(3):169-74.
    • 15. Reynolds NJ, Al-Daraji WI. Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. Clinical and Experimental Dermatology. 2002;27(7):555-61.
    • 16. Grawunder U, Zimmer D, Fugmann S, Schwarz K, Lieber MR. DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes. Molecular Cell. 1998;2:477-84.
    • 17. Riballo E, Kuhne M, Rief N, Doherty AJ, Smith GC, Recio MJ, et al. A pathway of double strand break rejoining dependent upon ATM, Artemis and proteins locating to γ-H2AX foci. Mol Cell. 2004 Dec 3;16:715-24.
    • 18. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA doublestranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273(10):5858-68.
    • 19. Rogakou EP, Boon C, Redon C, Bonner WM. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol. 1999;146(5):905-16.
    • 20. Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A. H2AX: the histone guardian of the genome. DNA Repair. 2004;3(8-9):959-67.
    • 21. Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, et al. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol. 2002;4(12):993-7.
    • 22. Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993;362:709-14.
    • 23. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair. 2003;2(9):955-69.
    • 24. Caldecott KW. Mammalian single-strand break repair: Mechanisms and links with chromatin. DNA Repair. 2007;6(4):443-53.
    • 25. Caldecott KW. Mammalian DNA single-strand break repair: an Xra(y)ted affair. BioEssays. 2001;23(5):447-55.
    • 26. Ahlers C, Kreideweiss S, Nordheim A, Ruhlmann A. Cyclosporin A inhibits Ca2+-mediated upregulation of the DNA repair enzyme DNA polymerase beta in human peripheral blood mononuclear cells. European Journal of Biochemistry. 1999;264(3):952-9.
    • 27. Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U, Nikolopoulos E, et al. A Severe Form of Human Combined Immunodeficiency Due to Mutations in DNA Ligase IV. J Immunol. 2006;176(8):5060-8.
    • 28. van der Burg M, van Veelen LR, Verkaik NS, Wiegant WW, Hartwig NG, Barendregt BH, et al. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest. 2006;116(1):137-45.
    • 29. Lobrich M, Jeggo PA. Harmonising the response to DSBs: a new string in the ATM bow. DNA Repair. 2005;4(7):749-59.
    • 30. Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO Journal. 1998;17(18):5497-508.
    • 31. Ruutu T, Niederwieser D, Gratwohl A, Apperley J. A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation. 1997;19(8):759-64.
    • 32. Deeg HJ, Socie G. Malignancies After Hematopoietic Stem Cell Transplantation: Many Questions, Some Answers. Blood. 1998;91(6):1833-44.
    • 33. Buell JF, Gross TG, Woodle, E Steve Malignancy after transplantation. Transplantation. 2005;80(2(S)):254-64.
    • 34. Tremblay F, Fernandes M, Habbab F, de Edwardes M, Loertscher R, Meterissian S. Malignancy after renal transplantation: Incidence and role of type of immunosuppression. Annals of Surgical Oncology. 2002;9(8):785-8.
    • 35. Herman M, Weinstein T, Korzets A, Chagnac A, Ori Y, Zevin D, et al. Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. Journal of Laboratory and Clinical Medicine. 2001;137(1):14-20.
    • 36. Herman M, Ori Y, Chagnac A, Weinstein T, Korzets A, Zevin D, et al. DNA repair in mononuclear cells: Role of serine/threonine phosphatases. Journal of Laboratory and Clinical Medicine. 2002;140(4):255-62.
    • 37. Yarosh DB, Pena AV, Nay SL, Canning MT, Brown DA. Calcineurin Inhibitors Decrease DNA Repair and Apoptosis in Human Keratinocytes Following Ultraviolet B Irradiation. J Investig Dermatol. 2005;125(5):1020-5.
    • 38. O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu Y-Z, Harwood CA, et al. Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage. Science. 2005;309(5742):1871-4.
    • 39. Karran P. Thiopurines, DNA damage, DNA repair and therapy-related cancer. Br Med Bull. 2006;79-80(1):153-70.
    • 40. Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, et al. H2AX Prevents DNA Breaks from Progressing to Chromosome Breaks and Translocations. Molecular Cell. 2006;21(2):201-14.
    • 41. Franco S, Alt FW, Manis JP. Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair. 2006;5(9-10):1030-41.
    • 42. Couedel C, Mills KD, Barchi M, Shen L, Olshen A, Johnson RD, et al. Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells. Genes Dev. 2004 Jun 1;18(11):1293-304.
    • 43. Kolb HJ, Socie G, Duell T, Van Lint MT, Tichelli A, Apperley JF, et al. Malignant Neoplasms in Long-Term Survivors of Bone Marrow Transplantation. Ann Intern Med. 1999;131(10):738-44.
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article