DOI QR코드

DOI QR Code

Role of RUNX Family Transcription Factors in DNA Damage Response

  • Samarakkody, Ann Sanoji (Department of Pediatric Hematology-Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School) ;
  • Shin, Nah-Young (Department of Pediatric Hematology-Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School) ;
  • Cantor, Alan B. (Department of Pediatric Hematology-Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School)
  • Received : 2019.12.05
  • Accepted : 2019.12.12
  • Published : 2020.02.29

Abstract

Cells are constantly exposed to endogenous and exogenous stresses that can result in DNA damage. In response, they have evolved complex pathways to maintain genomic integrity. RUNX family transcription factors (RUNX1, RUNX2, and RUNX3 in mammals) are master regulators of development and differentiation, and are frequently dysregulated in cancer. A growing body of research also implicates RUNX proteins as regulators of the DNA damage response, often acting in conjunction with the p53 and Fanconi anemia pathways. In this review, we discuss the functional role and mechanisms involved in RUNX factor mediated response to DNA damage and other cellular stresses. We highlight the impact of these new findings on our understanding of cancer predisposition associated with RUNX factor dysregulation and their implications for designing novel approaches to prevent cancer formation in affected individuals.

Keywords

References

  1. Akech, J., Wixted, J.J., Bedard, K., van der Deen, M., Hussain, S., Guise, T.A., van Wijnen, A.J., Stein, J.L., Languino, L.R., Altieri, D.C., et al. (2010). Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene 29, 811-821. https://doi.org/10.1038/onc.2009.389
  2. Alcalay, M., Meani, N., Gelmetti, V., Fantozzi, A., Fagioli, M., Orleth, A., Riganelli, D., Sebastiani, C., Cappelli, E., Casciari, C., et al. (2003). Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J. Clin. Invest. 112, 1751-1761. https://doi.org/10.1172/JCI17595
  3. Antony-Debre, I., Manchev, V.T., Balayn, N., Bluteau, D., Tomowiak, C., Legrand, C., Langlois, T., Bawa, O., Tosca, L., Tachdjian, G., et al. (2015). Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood 125, 930-940. https://doi.org/10.1182/blood-2014-06-585513
  4. Bae, S.C. and Choi, J.K. (2004). Tumor suppressor activity of RUNX3. Oncogene 23, 4336-4340. https://doi.org/10.1038/sj.onc.1207286
  5. Bellissimo, D.C. and Speck, N.A. (2017). RUNX1 mutations in inherited and sporadic leukemia. Front. Cell Dev. Biol. 5, 111. https://doi.org/10.3389/fcell.2017.00111
  6. Berardi, M.J., Sun, C., Zehr, M., Abildgaard, F., Peng, J., Speck, N.A., and Bushweller, J.H. (1999). The Ig fold of the core binding factor alpha Runt domain is a member of a family of structurally and functionally related Igfold DNA-binding domains. Structure 7, 1247-1256. https://doi.org/10.1016/S0969-2126(00)80058-1
  7. Blyth, K., Cameron, E.R., and Neil, J.C. (2005). The RUNX genes: gain or loss of function in cancer. Nat. Rev. Cancer 5, 376-387. https://doi.org/10.1038/nrc1607
  8. Blyth, K., Vaillant, F., Hanlon, L., Mackay, N., Bell, M., Jenkins, A., Neil, J.C., and Cameron, E.R. (2006). Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo. Cancer Res. 66, 2195-2201. https://doi.org/10.1158/0008-5472.CAN-05-3558
  9. Cai, X., Gao, L., Teng, L., Ge, J., Oo, Z.M., Kumar, A.R., Gilliland, D.G., Mason, P.J., Tan, K., and Speck, N.A. (2015). Runx1 deficiency decreases ribosome biogenesis and confers stress resistance to hematopoietic stem and progenitor cells. Cell Stem Cell 17, 165-177. https://doi.org/10.1016/j.stem.2015.06.002
  10. Calo, E., Quintero-Estades, J.A., Danielian, P.S., Nedelcu, S., Berman, S.D., and Lees, J.A. (2010). Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110-1114. https://doi.org/10.1038/nature09264
  11. Chan, K.L., Palmai-Pallag, T., Ying, S., and Hickson, I.D. (2009). Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat. Cell Biol. 11, 753-760. https://doi.org/10.1038/ncb1882
  12. Chen, F., Wang, M., Bai, J., Liu, Q., Xi, Y., Li, W., and Zheng, J. (2014). Role of RUNX3 in suppressing metastasis and angiogenesis of human prostate cancer. PLoS One 9, e86917. https://doi.org/10.1371/journal.pone.0086917
  13. Cheng, Q. and Chen, J. (2010). Mechanism of p53 stabilization by ATM after DNA damage. Cell Cycle 9, 472-478. https://doi.org/10.4161/cc.9.3.10556
  14. Chi, X.Z., Kim, J., Lee, Y.H., Lee, J.W., Lee, K.S., Wee, H., Kim, W.J., Park, W.Y., Oh, B.C., Stein, G.S., et al. (2009). Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination. Cancer Res. 69, 8111-8119. https://doi.org/10.1158/0008-5472.CAN-09-1057
  15. Chi, X.Z., Lee, J.W., Lee, Y.S., Park, I.Y., Ito, Y., and Bae, S.C. (2017). Runx3 plays a critical role in restriction-point and defense against cellular transformation. Oncogene 36, 6884-6894. https://doi.org/10.1038/onc.2017.290
  16. Choi, A., Illendula, A., Pulikkan, J.A., Roderick, J.E., Tesell, J., Yu, J., Hermance, N., Zhu, L.J., Castilla, L.H., Bushweller, J.H., et al. (2017). RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. Blood 130, 1722-1733. https://doi.org/10.1182/blood-2017-03-775536
  17. Chuang, L.S. and Ito, Y. (2010). RUNX3 is multifunctional in carcinogenesis of multiple solid tumors. Oncogene 29, 2605-2615. https://doi.org/10.1038/onc.2010.88
  18. Dronkert, M.L. and Kanaar, R. (2001). Repair of DNA interstrand cross-links. Mutat. Res. 486, 217-247. https://doi.org/10.1016/S0921-8777(01)00092-1
  19. Ernst, T., Chase, A., Zoi, K., Waghorn, K., Hidalgo-Curtis, C., Score, J., Jones, A., Grand, F., Reiter, A., Hochhaus, A., et al. (2010). Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms. Haematologica 95, 1473-1480. https://doi.org/10.3324/haematol.2010.021808
  20. Esposito, M.T., Zhao, L., Fung, T.K., Rane, J.K., Wilson, A., Martin, N., Gil, J., Leung, A.Y., Ashworth, A., and So, C.W. (2015). Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat. Med. 21, 1481-1490. https://doi.org/10.1038/nm.3993
  21. Fischer, M. (2017). Census and evaluation of p53 target genes. Oncogene 36, 3943-3956. https://doi.org/10.1038/onc.2016.502
  22. Forster, V.J., Nahari, M.H., Martinez-Soria, N., Bradburn, A.K., Ptasinska, A., Assi, S.A., Fordham, S.E., McNeil, H., Bonifer, C., Heidenreich, O., et al. (2016). The leukemia-associated RUNX1/ETO oncoprotein confers a mutator phenotype. Leukemia 30, 250-253.
  23. Forus, A., Weghuis, D.O., Smeets, D., Fodstad, O., Myklebost, O., and Geurts van Kessel, A. (1995). Comparative genomic hybridization analysis of human sarcomas: II. identification of novel amplicons at 6p and 17p in osteosarcomas. Genes Chromosomes Cancer 14, 15-21. https://doi.org/10.1002/gcc.2870140104
  24. Godley, L.A. (2014). Inherited predisposition to acute myeloid leukemia. Semin. Hematol. 51, 306-321. https://doi.org/10.1053/j.seminhematol.2014.08.001
  25. Haneline, L.S., Broxmeyer, H.E., Cooper, S., Hangoc, G., Carreau, M., Buchwald, M., and Clapp, D.W. (1998). Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/- mice. Blood 91, 4092-4098. https://doi.org/10.1182/blood.V91.11.4092
  26. Harada, Y. and Harada, H. (2011). Molecular mechanisms that produce secondary MDS/AML by RUNX1/AML1 point mutations. J. Cell. Biochem. 112, 425-432. https://doi.org/10.1002/jcb.22974
  27. Imai, Y., Kurokawa, M., Tanaka, K., Friedman, A.D., Ogawa, S., Mitani, K., Yazaki, Y., and Hirai, H. (1998). TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation. Biochem. Biophys. Res. Commun. 252, 582-589. https://doi.org/10.1006/bbrc.1998.9705
  28. Ito, Y., Bae, S.C., and Chuang, LS. (2015). The RUNX family: developmental regulators in cancer. Nat. Rev. Cancer 15, 81-95. https://doi.org/10.1038/nrc3877
  29. Jongmans, M.C., Kuiper, R.P., Carmichael, C.L., Wilkins, E.J., Dors, N., Carmagnac, A., Schouten-van Meeteren, A.Y., Li, X., Stankovic, M., Kamping, E., et al. (2010). Novel RUNX1 mutations in familial platelet disorder with enhanced risk for acute myeloid leukemia: clues for improved identification of the FPD/AML syndrome. Leukemia 24, 242-246. https://doi.org/10.1038/leu.2009.210
  30. Kastan, M.B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R.W. (1991). Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304-6311.
  31. Kelsall, I.R., Langenick, J., MacKay, C., Patel, K.J., and Alpi, A.F. (2012). The Fanconi anaemia components UBE2T and FANCM are functionally linked to nucleotide excision repair. PLoS One 7, e36970. https://doi.org/10.1371/journal.pone.0036970
  32. Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R.T., Gao, Y.H., Inada, M., et al. (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755-764. https://doi.org/10.1016/S0092-8674(00)80258-5
  33. Krejci, O., Wunderlich, M., Geiger, H., Chou, F.S., Schleimer, D., Jansen, M., Andreassen, P.R., and Mulloy, J.C. (2008). p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death. Blood 111, 2190-2199. https://doi.org/10.1182/blood-2007-06-093682
  34. Kuo, M.C., Liang, D.C., Huang, C.F., Shih, Y.S., Wu, J.H., Lin, T.L., and Shih, L.Y. (2009). RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation. Leukemia 23, 1426-1431. https://doi.org/10.1038/leu.2009.48
  35. Lamarche, B.J., Orazio, N.I., and Weitzman, M.D. (2010). The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett. 584, 3682-3695. https://doi.org/10.1016/j.febslet.2010.07.029
  36. Lau, C.C., Harris, C.P., Lu, X.Y., Perlaky, L., Gogineni, S., Chintagumpala, M., Hicks, J., Johnson, M.E., Davino, N.A., Huvos, A.G., et al. (2004). Frequent amplification and rearrangement of chromosomal bands 6p12-p21 and 17p11.2 in osteosarcoma. Genes Chromosomes Cancer. 39, 11-21. https://doi.org/10.1002/gcc.10291
  37. Lawley, P.D. and Phillips, D.H. (1996). DNA adducts from chemotherapeutic agents. Mutat. Res. 355, 13-40. https://doi.org/10.1016/0027-5107(96)00020-6
  38. Lee, J.W., Kim, D.M., Jang, J.W., Park, T.G., Song, S.H., Lee, Y.S., Chi, X.Z., Park, I.Y., Hyun, J.W., Ito, Y., et al. (2019). RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restrictionpoint. Nat. Commun. 10, 1897. https://doi.org/10.1038/s41467-019-09810-w
  39. Lee, S.H., Manandhar, S., and Lee, Y.M. (2017). Roles of RUNX in hypoxiainduced responses and angiogenesis. Adv. Exp. Med. Biol. 962, 449-469. https://doi.org/10.1007/978-981-10-3233-2_27
  40. Levanon, D. and Groner, Y. (2009). Runx3-deficient mouse strains circa 2008: resemblance and dissimilarity. Blood Cells Mol. Dis. 43, 1-5. https://doi.org/10.1016/j.bcmd.2009.01.009
  41. Liddiard, K., Hills, R., Burnett, A.K., Darley, R.L., and Tonks, A. (2010). OGG1 is a novel prognostic indicator in acute myeloid leukaemia. Oncogene 29, 2005-2012. https://doi.org/10.1038/onc.2009.462
  42. Liu, Y., Tavana, O., and Gu, W. (2019). p53 modifications: exquisite decorations of the powerful guardian. J. Mol. Cell Biol. 11, 564-577. https://doi.org/10.1093/jmcb/mjz060
  43. Lohrum, M.A., Woods, D.B., Ludwig, R.L., Bálint, E., and Vousden, K.H. (2001). C-terminal ubiquitination of p53 contributes to nuclear export. Mol. Cell. Biol. 21, 8521-8532. https://doi.org/10.1128/MCB.21.24.8521-8532.2001
  44. Lopez-Martinez, D., Liang, C.C., and Cohn, M.A. (2016). Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway. Cell. Mol. Life Sci. 73, 3097-3114. https://doi.org/10.1007/s00018-016-2218-x
  45. Manandhar, S. and Lee, Y.M. (2018). Emerging role of RUNX3 in the regulation of tumor microenvironment. BMB Rep. 51, 174-181. https://doi.org/10.5483/BMBRep.2018.51.4.033
  46. Mangan, J.K. and Speck, N.A. (2011). RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing, a story 40 years in the making. Crit. Rev. Oncog. 16, 77-91. https://doi.org/10.1615/CritRevOncog.v16.i1-2.80
  47. Marchenko, N.D., Hanel, W., Li, D., Becker, K., Reich, N., and Moll, U.M. (2010). Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding. Cell Death Differ. 17, 255-267. https://doi.org/10.1038/cdd.2009.173
  48. Marechal A. and Zou, L. (2013). DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 5, a012716. https://doi.org/10.1101/cshperspect.a012716
  49. Martin, J.W., Zielenska, M., Stein, G.S., van Wijnen, A.J., and Squire, J.A. (2011). The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma 2011, 282745. https://doi.org/10.1155/2011/282745
  50. McHugh, P.J., Spanswick, V.J., and Hartley, J.A. (2001). Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol. 2, 483-490. https://doi.org/10.1016/S1470-2045(01)00454-5
  51. Meetei, A.R., de Winter, J.P., Medhurst, A.L., Wallisch, M., Waisfisz, Q., van de Vrugt, H.J., Oostra, A.B., Yan, Z., Ling, C., Bishop, C.E., et al. (2003). A novel ubiquitin ligase is deficient in Fanconi anemia. Nat. Genet. 35, 165-170. https://doi.org/10.1038/ng1241
  52. Moldovan, G.L. and D'Andrea, A.D. (2009). How the fanconi anemia pathway guards the genome. Annu. Rev. Genet. 43, 223-249. https://doi.org/10.1146/annurev-genet-102108-134222
  53. Naim, V. and Rosselli, F. (2009). The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat. Cell Biol. 11, 761-768. https://doi.org/10.1038/ncb1883
  54. Nguyen, T.V., Riou, L., Aoufouchi, S., and Rosselli, F. (2014). Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells. J. Exp. Med. 211, 1011-1018. https://doi.org/10.1084/jem.20131637
  55. Niraj, J., Farkkila, A., and D'Andrea, A.D. (2019). The Fanconi anemia pathway in cancer. Annu. Rev. Cancer Biol. 3, 457-478. https://doi.org/10.1146/annurev-cancerbio-030617-050422
  56. O'Keefe, K., Li, H., and Zhang, Y. (2003). Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination. Mol. Cell. Biol. 23, 6396-6405. https://doi.org/10.1128/MCB.23.18.6396-6405.2003
  57. Osato, M. (2004). Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 23, 4284-4296. https://doi.org/10.1038/sj.onc.1207779
  58. Otto, F., Thornell, A.P., Crompton, T., Denzel, A., Gilmour, K.C., Rosewell, I.R., Stamp, G.W., Beddington, R.S., Mundlos, S., Olsen, B.R., et al. (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765-771. https://doi.org/10.1016/S0092-8674(00)80259-7
  59. Owen, C.J., Toze, C.L., Koochin, A., Forrest, D.L., Smith, C.A., Stevens, J.M., Jackson, S.C., Poon, M.C., Sinclair, G.D., Leber, B., et al. (2008). Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 112, 4639-4645. https://doi.org/10.1182/blood.v112.11.4639.4639
  60. Ozaki, T., Nakagawara, A., and Nagase, H. (2013b). RUNX family participates in the regulation of p53-dependent DNA damage response. Int. J. Genomics 2013, 271347. https://doi.org/10.1155/2013/271347
  61. Ozaki, T., Nakamura, M., Ogata, T., Sang, M., Yoda, H., Hiraoka, K., Sang, M., and Shimozato, O. (2016). Depletion of pro-oncogenic RUNX2 enhances gemcitabine (GEM) sensitivity of p53-mutated pancreatic cancer Panc-1 cells through the induction of pro-apoptotic TAp63. Oncotarget 7, 71937-71950. https://doi.org/10.18632/oncotarget.12433
  62. Ozaki, T., Wu, D., Sugimoto, H., Nagase, H., and Nakagawara, A. (2013a). Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage. Cell Death Dis. 4, e610. https://doi.org/10.1038/cddis.2013.127
  63. Pratap, J., Wixted, J.J., Gaur, T., Zaidi, S.K., Dobson, J., Gokul, K.D., Hussain, S., van Wijnen, A.J., Stein, J.L., Stein, G.S., et al. (2008). Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res. 68, 7795-7802. https://doi.org/10.1158/0008-5472.CAN-08-1078
  64. Qiao, F., Mi, J., Wilson, J.B., Zhi, G., Bucheimer, N.R., Jones, N.J., and Kupfer, G.M. (2004). Phosphorylation of fanconi anemia (FA) complementation group G protein, FANCG, at serine 7 is important for function of the FA pathway. J. Biol. Chem. 279, 46035-46045. https://doi.org/10.1074/jbc.M408323200
  65. Reed, S.M. and Quelle, D.E. (2014). p53 acetylation: regulation and consequences. Cancers (Basel) 7, 30-69. https://doi.org/10.3390/cancers7010030
  66. Renaud, E., Barascu, A., and Rosselli, F. (2016). Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells. Nucleic Acids Res. 44, 648-656. https://doi.org/10.1093/nar/gkv1019
  67. Rickman, K.A., Lach, F.P., Abhyankar, A., Donovan, F.X., Sanborn, E.M., Kennedy, J.A., Sougnez, C., Gabriel, S.B., Elemento, O., Chandrasekharappa, S.C., et al. (2015). Deficiency of UBE2T, the E2 ubiquitin ligase necessary for FANCD2 and FANCI ubiquitination, causes FA-T subtype of Fanconi anemia. Cell Rep. 12, 35-41. https://doi.org/10.1016/j.celrep.2015.06.014
  68. Rodriguez, A. and D'Andrea, A. (2017). Fanconi anemia pathway. Curr. Biol. 27, R986-R988. https://doi.org/10.1016/j.cub.2017.07.043
  69. Rodriguez, M.S., Desterro, J.M., Lain, S., Lane, D.P., and Hay, R.T. (2000). Multiple C-terminal lysine residues target p53 for ubiquitin-proteasomemediated degradation. Mol. Cell. Biol. 20, 8458-8467. https://doi.org/10.1128/MCB.20.22.8458-8467.2000
  70. Roos, A., Satterfield, L., Zhao, S., Fuja, D., Shuck, R., Hicks, M.J., Donehower, L.A., and Yustein, J.T. (2015). Loss of Runx2 sensitises osteosarcoma to chemotherapy-induced apoptosis. Br. J. Cancer 113, 1289-1297. https://doi.org/10.1038/bjc.2015.305
  71. Satoh, Y., Matsumura, I., Tanaka, H., Harada, H., Harada, Y., Matsui, K., Shibata, M., Mizuki, M., and Kanakura, Y. (2012). C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells. Leukemia 26, 303-311. https://doi.org/10.1038/leu.2011.202
  72. Schindler, D. and Hoehn, H. (1988). Fanconi anemia mutation causes cellular susceptibility to ambient oxygen. Am. J. Hum. Genet. 43, 429-435.
  73. Shin, M.H., He, Y., Marrogi, E., Piperdi, S., Ren, L., Khanna, C., Gorlick, R., Liu, C., and Huang, J. (2016). A RUNX2-mediated epigenetic regulation of the survival of p53 defective cancer cells. PLoS Genet 12, e1005884. https://doi.org/10.1371/journal.pgen.1005884
  74. Singh, T.R., Ali, A.M., Paramasivam, M., Pradhan, A., Wahengbam, K., Seidman, M.M., and Meetei, A.R. (2013). ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer Res. 73, 4300-4310. https://doi.org/10.1158/0008-5472.CAN-12-3976
  75. Song, W.J., Sullivan, M.G., Legare, R.D., Hutchings, S., Tan, X., Kufrin, D., Ratajczak, J., Resende, I.C., Haworth, C., Hock, R., et al. (1999). Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat. Genet. 23, 166-175. https://doi.org/10.1038/13793
  76. Sugimoto, H., Nakamura, M., Yoda, H., Hiraoka, K., Shinohara, K., Sang, M., Fujiwara, K., Shimozato, O., Nagase, H., and Ozaki, T. (2015). Silencing of RUNX2 enhances gemcitabine sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells through the stimulation of TAp63-mediated cell death. Cell Death Discov. 1, 15010. https://doi.org/10.1038/cddiscovery.2015.10
  77. Sun, C., Chang, L., and Zhu, X. (2017). Pathogenesis of ETV6/RUNX1- positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget 8, 35445-35459. https://doi.org/10.18632/oncotarget.16367
  78. Tay, L.S., Krishnan, V., Sankar, H., Chong, Y.L., Chuang, L.S.H., Tan, T.Z., Kolinjivadi, A.M., Kappei, D., and Ito, Y. (2018). RUNX poly(ADP-ribosyl) ation and BLM interaction facilitate the Fanconi anemia pathway of DNA repair. Cell Rep. 24, 1747-1755. https://doi.org/10.1016/j.celrep.2018.07.038
  79. Wang, C.Q., Krishnan, V., Tay, L.S., Chin, D.W., Koh, C.P., Chooi, J.Y., Nah, G.S., Du, L., Jacob, B., Yamashita, N., et al. (2014). Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects. Cell Rep. 8, 767-782. https://doi.org/10.1016/j.celrep.2014.06.046
  80. Wang, Q., Stacy, T., Binder, M., Marin-Padilla, M., Sharpe, A.H., and Speck, N.A. (1996). Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc. Natl. Acad. Sci. U. S. A. 93, 3444-3449. https://doi.org/10.1073/pnas.93.8.3444
  81. Wang, W. (2007). Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat. Rev. Genet. 8, 735-748. https://doi.org/10.1038/nrg2159
  82. Westendorf, J.J., Zaidi, S.K., Cascino, J.E., Kahler, R., van Wijnen, A.J., Lian, J.B., Yoshida, M., Stein, G.S., and Li, X. (2002). Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Mol. Cell. Biol. 22, 7982-7992. https://doi.org/10.1128/MCB.22.22.7982-7992.2002
  83. Whitney, M.A., Royle, G., Low, M.J., Kelly, M.A., Axthelm, M.K., Reifsteck, C., Olson, S., Braun, R.E., Heinrich, M.C., Rathbun, R.K., et al. (1996). Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood 88, 49-58. https://doi.org/10.1182/blood.V88.1.49.49
  84. Wilson, J.B., Blom, E., Cunningham, R., Xiao, Y., Kupfer, G.M., and Jones, N.J. (2010). Several tetratricopeptide repeat (TPR) motifs of FANCG are required for assembly of the BRCA2/D1-D2-G-X3 complex, FANCD2 monoubiquitylation and phleomycin resistance. Mutat. Res. 689, 12-20. https://doi.org/10.1016/j.mrfmmm.2010.04.003
  85. Wotton, S.F., Blyth, K., Kilbey, A., Jenkins, A., Terry, A., Bernardin-Fried, F., Friedman, A.D., Baxter, E.W., Neil, J.C., and Cameron, E.R. (2004). RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53. Oncogene 23, 5476-5486. https://doi.org/10.1038/sj.onc.1207729
  86. Wu, D., Ozaki, T., Yoshihara, Y., Kubo, N., and Nakagawara, A. (2013). Runtrelated transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation. J. Biol. Chem. 288, 1353-1364. https://doi.org/10.1074/jbc.M112.402594
  87. Wysokinski, D., Blasiak, J., and Pawlowska, E. (2015). Role of RUNX2 in breast carcinogenesis. Int. J. Mol. Sci. 16, 20969-20993. https://doi.org/10.3390/ijms160920969
  88. Yamada, C., Ozaki, T., Ando, K., Suenaga, Y., Inoue, K., Ito, Y., Okoshi, R., Kageyama, H., Kimura, H., Miyazaki, M., et al. (2010). RUNX3 modulates DNA damage-mediated phosphorylation of tumor suppressor p53 at Ser-15 and acts as a co-activator for p53. J. Biol. Chem. 285, 16693-16703. https://doi.org/10.1074/jbc.M109.055525
  89. Yan, J., Liu, Y., Lukasik, S.M., Speck, N.A., and Bushweller, J.H. (2004). CBF${\beta}$ allosterically regulates the Runx1 Runt domain via a dynamic conformational equilibrium. Nat. Struct. Mol. Biol. 11, 901-906. https://doi.org/10.1038/nsmb819
  90. Zhou, X., Cao, B., and Lu, H. (2017). Negative auto-regulators trap p53 in their web. J. Mol. Cell Biol. 9, 62-68. https://doi.org/10.1093/jmcb/mjx001
  91. Zou, Y., Liu, Y., Wu, X., and Shell, S.M. (2006). Functions of human replication protein A (RPA): from DNA replication to DNA damage and stress responses. J. Cell. Physiol. 208, 267-273. https://doi.org/10.1002/jcp.20622

Cited by

  1. DGCR8/miR-106 Axis Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinomas by Downregulating RUNX3 vol.7, 2020, https://doi.org/10.3389/fmed.2020.582097
  2. The microRNA-130a-5p/RUNX2/STK32A network modulates tumor invasive and metastatic potential in non-small cell lung cancer vol.20, pp.1, 2020, https://doi.org/10.1186/s12885-020-07056-0
  3. Runx Transcription Factors in T Cells-What Is Beyond Thymic Development? vol.12, 2020, https://doi.org/10.3389/fimmu.2021.701924
  4. Sweet Melody or Jazz? Transcription Around DNA Double-Strand Breaks vol.8, 2020, https://doi.org/10.3389/fmolb.2021.655786
  5. Runt‐related transcription factor 1 (Runx1) aggravates pathological cardiac hypertrophy by promoting p53 expression vol.25, pp.16, 2021, https://doi.org/10.1111/jcmm.16704
  6. B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations vol.5, pp.16, 2021, https://doi.org/10.1182/bloodadvances.2021004653
  7. Expression patterns and prognostic value of RUNX genes in kidney cancer vol.11, pp.1, 2020, https://doi.org/10.1038/s41598-021-94294-2