Determination of the DNA Repair Pathways Utilised by Acute Lymphoblastic Leukaemia Cells Following Daunorubicin Treatment

Overview

Journal BMC Res Notes

Publisher Biomed Central

Specialties Biology
General Medicine

Date 2019 Sep 26

PMID 31551083

Citations 2

Authors

Hussain Mubarak Al-Aamri

Helen R Irving

Terri Meehan-Andrews

Christopher Bradley

Affiliations

Soon will be listed here.

Abstract

Objective: DNA double strand breaks (DNA-DSBs) are among the most lethal DNA lesions leading to genomic instability and repaired by either homologous recombination (HR) or the non-homologous end joining (NHEJ) mechanisms. The purpose of this study was to assess the importance and the level of activation of non-homologous end joining (NHEJ) and homologous recombination (HR) DNA repair pathways in three cell lines, CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes following treatment with chemotherapy agent daunorubicin.

Results: The Gamma histone H2AX (γH2AX) assay was used assess the effects of DNA-PK inhibitor NU7026 and RAD51 inhibitor RI-2 on repair of DNA-DSB following treatment with daunorubicin. In all cell lines, the NHEJ DNA repair pathway appeared more rapid and efficient. MOLT-4 and CCFR-CEM cells utilised both NHEJ and HR pathways for DNA-DSB repair. Whereas, SUP-B15 cells utilised only NHEJ for DSB repair, suggestive of a deficiency in HR repair pathways.

Citing Articles

Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia-positive lymphoid leukemia to tyrosine kinase inhibitors.

Komorowski L, Dabkowska A, Madzio J, Pastorczak A, Szczygiel K, Janowska M Hemasphere. 2024; 8(3):e56.

PMID: 38486859 PMC: 10938465. DOI: 10.1002/hem3.56.

Intrinsic and extrinsic apoptosis responses in leukaemia cells following daunorubicin treatment.

Al-Aamri H, Irving H, Bradley C, Meehan-Andrews T BMC Cancer. 2021; 21(1):438.

PMID: 33879127 PMC: 8059319. DOI: 10.1186/s12885-021-08167-y.

References

Walker J, Corpina R, Goldberg J . Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature. 2001; 412(6847):607-14. DOI: 10.1038/35088000. View

MacPhail S, Banath J, Yu T, Chu E, Lambur H, Olive P . Expression of phosphorylated histone H2AX in cultured cell lines following exposure to X-rays. Int J Radiat Biol. 2003; 79(5):351-8. DOI: 10.1080/0955300032000093128. View

Veuger S, Curtin N, Richardson C, Smith G, Durkacz B . Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res. 2003; 63(18):6008-15. View

King M, Marks J, Mandell J . Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003; 302(5645):643-6. DOI: 10.1126/science.1088759. View

Willmore E, de Caux S, Sunter N, Tilby M, Jackson G, Austin C . A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. Blood. 2004; 103(12):4659-65. DOI: 10.1182/blood-2003-07-2527. View

Wang H, Wang M, Wang H, Bocker W, Iliakis G . Complex H2AX phosphorylation patterns by multiple kinases including ATM and DNA-PK in human cells exposed to ionizing radiation and treated with kinase inhibitors. J Cell Physiol. 2004; 202(2):492-502. DOI: 10.1002/jcp.20141. View

Falck J, Coates J, Jackson S . Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature. 2005; 434(7033):605-11. DOI: 10.1038/nature03442. View

Nutley B, Smith N, Hayes A, Kelland L, Brunton L, Golding B . Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Br J Cancer. 2005; 93(9):1011-8. PMC: 2361671. DOI: 10.1038/sj.bjc.6602823. View

Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N . Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006; 22(6):719-729. DOI: 10.1016/j.molcel.2006.05.022. View

10.

Stiff T, Walker S, Cerosaletti K, Goodarzi A, Petermann E, Concannon P . ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J. 2006; 25(24):5775-82. PMC: 1698893. DOI: 10.1038/sj.emboj.7601446. View

11.

Amrein L, Loignon M, Goulet A, Dunn M, Jean-Claude B, Aloyz R . Chlorambucil cytotoxicity in malignant B lymphocytes is synergistically increased by 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026)-mediated inhibition of DNA double-strand break repair via inhibition of DNA-dependent protein kinase. J Pharmacol Exp Ther. 2007; 321(3):848-55. DOI: 10.1124/jpet.106.118356. View

12.

Uematsu N, Weterings E, Yano K, Morotomi-Yano K, Jakob B, Taucher-Scholz G . Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks. J Cell Biol. 2007; 177(2):219-29. PMC: 2064131. DOI: 10.1083/jcb.200608077. View

13.

Mao Z, Bozzella M, Seluanov A, Gorbunova V . Comparison of nonhomologous end joining and homologous recombination in human cells. DNA Repair (Amst). 2008; 7(10):1765-71. PMC: 2695993. DOI: 10.1016/j.dnarep.2008.06.018. View

14.

Williams E, Klingler R, Ponnaiya B, Hardt T, Schrock E, Lees-Miller S . Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence. Cancer Res. 2009; 69(5):2100-7. PMC: 3595006. DOI: 10.1158/0008-5472.CAN-08-2854. View

15.

Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B . PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009; 19(6):524-9. PMC: 2750839. DOI: 10.1016/j.cub.2009.02.018. View

16.

Tomimatsu N, Mukherjee B, Burma S . Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells. EMBO Rep. 2009; 10(6):629-35. PMC: 2711839. DOI: 10.1038/embor.2009.60. View

17.

Lempiainen H, Halazonetis T . Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J. 2009; 28(20):3067-73. PMC: 2752028. DOI: 10.1038/emboj.2009.281. View

18.

Shibata A, Conrad S, Birraux J, Geuting V, Barton O, Ismail A . Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J. 2011; 30(6):1079-92. PMC: 3061033. DOI: 10.1038/emboj.2011.27. View

19.

Begg A, Stewart F, Vens C . Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer. 2011; 11(4):239-53. DOI: 10.1038/nrc3007. View

20.

Brandsma I, Gent D . Pathway choice in DNA double strand break repair: observations of a balancing act. Genome Integr. 2012; 3(1):9. PMC: 3557175. DOI: 10.1186/2041-9414-3-9. View