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The PHD3 domain of MLL acts as a CYP33-regulated switch between MLL-mediated activation and repression .

Park S, Osmers U, Raman G, Schwantes RH, Diaz MO, Bushweller JH
Biochemistry 49 6576-86 (2010)
Cited: 43 times
EuropePMC logo PMID: 20677832

Abstract

The mixed lineage leukemia (MLL) gene plays a critical role in epigenetic regulation of gene expression and is a frequent target of chromosomal translocations leading to leukemia. MLL plant homeodomain 3 (PHD3) is lost in all MLL translocation products, and reinsertion of PHD3 into MLL fusion proteins abrogates their transforming activity. PHD3 has been shown to interact with the RNA-recognition motif (RRM) domain of human nuclear Cyclophilin33 (CYP33). Here, we show that CYP33 mediates downregulation of the expression of MLL target genes HOXC8, HOXA9, CDKN1B, and C-MYC, in a proline isomerase-dependent manner. This downregulation correlates with the reduction of trimethylated lysine 4 of histone H3 (H3K4me3) and histone H3 acetylation. We have structurally characterized both the PHD3 and CYP33 RRM domains and analyzed their binding to one another. The PHD3 domain binds H3K4me3 (preferentially) and the CYP33 RRM domain at distinct sites. Our binding data show that binding of H3K4me3 to PHD3 and binding of the CYP33 RRM domain to PHD3 are mutually inhibitory, implying that PHD3 is a molecular switch for the transition between activation and repression of target genes. To explore the possible mechanism of CYP33/PHD3-mediated repression, we have analyzed the CYP33 proline isomerase activity on various H3 and H4 peptides and shown selectivity for two sites in H3. Our results provide a possible mechanism for the MLL PHD3 domain to act as a switch between activation and repression.

Reviews - 2kyx mentioned but not cited (2)

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  2. Structural and Functional Insights into Human Nuclear Cyclophilins. Rajiv C, Davis TL. Biomolecules 8 E161 (2018)

Articles - 2kyx mentioned but not cited (3)

  1. The PHD3 domain of MLL acts as a CYP33-regulated switch between MLL-mediated activation and repression . Park S, Osmers U, Raman G, Schwantes RH, Diaz MO, Bushweller JH. Biochemistry 49 6576-6586 (2010)
  2. Crystal and solution structures of human oncoprotein Musashi-2 N-terminal RNA recognition motif 1. Lan L, Xing M, Kashipathy M, Douglas J, Gao P, Battaile K, Hanzlik R, Lovell S, Xu L. Proteins 88 573-583 (2020)
  3. Cyp33 binds AU-rich RNA motifs via an extended interface that competitively disrupts the gene repressive Cyp33-MLL1 interaction in vitro. Lloyd NR, Wuttke DS. PLoS One 16 e0237956 (2021)


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  2. Handpicking epigenetic marks with PHD fingers. Musselman CA, Kutateladze TG. Nucleic Acids Res 39 9061-9071 (2011)
  3. A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks. Patel DJ. Cold Spring Harb Perspect Biol 8 a018754 (2016)
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  5. Prolyl isomerases in gene transcription. Hanes SD. Biochim Biophys Acta 1850 2017-2034 (2015)
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  15. Aberrant Activity of Histone-Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis. Poreba E, Lesniewicz K, Durzynska J. Int J Mol Sci 21 E9340 (2020)
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  19. Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors. Ikeda D, Chi S, Uchiyama S, Nakamura H, Guo YM, Yamauchi N, Yuda J, Minami Y. Int J Mol Sci 23 5950 (2022)
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  2. Tandem PHD fingers of MORF/MOZ acetyltransferases display selectivity for acetylated histone H3 and are required for the association with chromatin. Ali M, Yan K, Lalonde ME, Degerny C, Rothbart SB, Strahl BD, Côté J, Yang XJ, Kutateladze TG. J Mol Biol 424 328-338 (2012)
  3. ECSASB2 mediates MLL degradation during hematopoietic differentiation. Wang J, Muntean AG, Hess JL. Blood 119 1151-1161 (2012)
  4. A subset of mixed lineage leukemia proteins has plant homeodomain (PHD)-mediated E3 ligase activity. Wang J, Muntean AG, Wu L, Hess JL. J Biol Chem 287 43410-43416 (2012)
  5. Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis. Ballabio E, Milne TA. Cancers (Basel) 4 904-944 (2012)
  6. Histone recognition and nuclear receptor co-activator functions of Drosophila cara mitad, a homolog of the N-terminal portion of mammalian MLL2 and MLL3. Chauhan C, Zraly CB, Parilla M, Diaz MO, Dingwall AK. Development 139 1997-2008 (2012)
  7. Cyclophilin A promotes non-small cell lung cancer metastasis via p38 MAPK. Guo Y, Jiang M, Zhao X, Gu M, Wang Z, Xu S, Yue W. Thorac Cancer 9 120-128 (2018)
  8. Inhibition of class I HDACs abrogates the dominant effect of MLL-AF4 by activation of wild-type MLL. Ahmad K, Katryniok C, Scholz B, Merkens J, Löscher D, Marschalek R, Steinhilber D. Oncogenesis 3 e127 (2014)
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  11. The basic tilted helix bundle domain of the prolyl isomerase FKBP25 is a novel double-stranded RNA binding module. Dilworth D, Upadhyay SK, Bonnafous P, Edoo AB, Bourbigot S, Pesek-Jardim F, Gudavicius G, Serpa JJ, Petrotchenko EV, Borchers CH, Nelson CJ, Mackereth CD. Nucleic Acids Res 45 11989-12004 (2017)
  12. Relatively favorable prognosis for MLL-rearranged childhood acute leukemia with reciprocal translocations. Yang L, Ding L, Liang J, Chen J, Tang Y, Xue H, Gu L, Shen S, Li B, Chen J. Pediatr Blood Cancer 65 e27266 (2018)
  13. The spliceosomal proteins PPIH and PRPF4 exhibit bi-partite binding. Rajiv C, Jackson SR, Cocklin S, Eisenmesser EZ, Davis TL. Biochem J 474 3689-3704 (2017)
  14. ASH2L-Promoted HOXC8 Gene Expression Plays a Role in Mixed Lineage Leukemia-Rearranged Acute Leukemia. Wu YJ, Li LX, Liu L, Zhao SS, Qiu HR, Wang H. Onco Targets Ther 13 381-387 (2020)
  15. The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11). Kundu A, Kowarz E, Marschalek R. Oncogene 40 5902-5912 (2021)
  16. Identification of Molecular Mechanisms Responsible for the MMP-9-1562C/T Dependent Differential Regulation of Matrix Metalloproteinase-9 Expression in Human Neuron-like Cells. Pabian-Jewuła S, Ambrożek-Latecka M, Brągiel-Pieczonka A, Nowicka K, Rylski M. Genes (Basel) 14 2028 (2023)
  17. RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription. Blatter M, Meylan C, Cléry A, Giambruno R, Nikolaev Y, Heidecker M, Solanki JA, Diaz MO, Gabellini D, Allain FH. Sci Adv 9 eadf5330 (2023)
  18. The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in Drosophila larvae. Johannessen JA, Formica M, Haukeland ALC, Bråthen NR, Al Outa A, Aarsund M, Therrien M, Enserink JM, Knævelsrud H. iScience 26 107726 (2023)


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