Home LiteratureArticle Details
PMID: 17967868 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis.

Molecular and cellular biology ·Vol. 28 ·No. 1 ·2008-01-00 ·Pages 397-409

Gupta A, Guerin-Peyrou TG, Sharma GG, Park C, Agarwal M, Ganju RK, Pandita S, Choi K, Sukumar S, Pandita RK, Ludwig T, Pandita TK

Abstract

The mammalian ortholog of the Drosophila MOF (males absent on the first) gene product is a histone H4 lysine 16-specific acetyltransferase. Recent studies have shown that depletion of human MOF (hMOF) in human cell lines leads to genomic instability, spontaneous chromosomal aberrations, cell cycle defects, altered nuclear morphology, reduced transcription of certain genes, and defective DNA damage response to ionizing radiation (IR). Here we show that MOF plays an essential role in mammals during embryogenesis and oncogenesis. Ablation of the mouse Mof gene (mMof) by gene targeting resulted in early embryonic lethality and cell death. Lethality correlated with the loss of H4 lysine 16 acetylation (H4K16ac) and could not be rescued by concomitant inactivation of ATM or p53. In comparison to primary cells or normal tissue, all immortalized human normal and tumor cell lines and primary tumors demonstrated similar or elevated hMOF and H4K16ac levels. Accordingly, MOF overexpression correlated with increased cellular proliferation, oncogenic transformation, and tumor growth. Thus, these data reveal that the acetylation of histone H4 at K16 by MOF is an epigenetic signature of cellular proliferation common to both embryogenesis and oncogenesis and that MOF is an essential factor for embryogenesis and oncogenesis.

MeSH Terms
Acetylation Animals Cell Proliferation Cell Transformation, Neoplastic/genetics,metabolism,pathology Cells, Cultured Drosophila Proteins/genetics,metabolism Drosophila melanogaster/embryology,genetics,metabolism Embryo Loss/genetics,metabolism Embryo, Mammalian/embryology,metabolism Gene Deletion Gene Expression Regulation Histone Acetyltransferases/genetics,metabolism Histones/metabolism Male Mice Nuclear Proteins/genetics,metabolism RNA, Messenger/genetics Tumor Suppressor Protein p53/metabolism
Chemicals
Drosophila Proteins Histones Nuclear Proteins RNA, Messenger Tumor Suppressor Protein p53 Histone Acetyltransferases KAT8 protein, human Kat8 protein, mouse mof protein, Drosophila
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Gupta Arun
Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108, USA.
Guerin-Peyrou T Geraldine
Sharma Girdhar G
Park Changwon
Agarwal Manjula
Ganju Ramesh K
Pandita Shruti
Choi Kyunghee
Sukumar Saraswati
Pandita Raj K
Ludwig Thomas
Pandita Tej K
References (50)
50 references, click to expand
  1. p53 and ATM: cell cycle, cell death, and cancer.
    Adv Cancer Res. 1997;71:1-25 PMID: 9111862
  2. hTERT associates with human telomeres and enhances genomic stability and DNA repair.
    Oncogene. 2003 Jan 9;22(1):131-46 PMID: 12527915
  3. Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila.
    Mol Cell. 2000 Feb;5(2):367-75 PMID: 10882077
  4. SAS-mediated acetylation of histone H4 Lys 16 is required for H2A.Z incorporation at subtelomeric regions in Saccharomyces cerevisiae.
    Genes Dev. 2006 Sep 15;20(18):2507-12 PMID: 16980580
  5. A multifaceted role for ATM in genome maintenance.
    Expert Rev Mol Med. 2003 Jun 20;5(16):1-21 PMID: 14987398
  6. Histone H4-K16 acetylation controls chromatin structure and protein interactions.
    Science. 2006 Feb 10;311(5762):844-7 PMID: 16469925
  7. A decade of histone acetylation: marking eukaryotic chromosomes with specific codes.
    J Biochem. 2005 Dec;138(6):647-62 PMID: 16428293
  8. Histones and histone modifications.
    Curr Biol. 2004 Jul 27;14(14):R546-51 PMID: 15268870
  9. Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division.
    Cancer Res. 1973 Dec;33(12):3231-8 PMID: 4357355
  10. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions.
    Science. 2004 Dec 17;306(5704):2084-7 PMID: 15528408
  11. Histone H4 acetylated at lysine 16 and proteins of the Drosophila dosage compensation pathway co-localize on the male X chromosome through mitosis.
    Chromosome Res. 1994 Sep;2(5):398-404 PMID: 7981944
  12. Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains.
    Biochem Biophys Res Commun. 1997 Aug 28;237(3):752-7 PMID: 9299439
  13. The drosophila MSL complex acetylates histone H4 at lysine 16, a chromatin modification linked to dosage compensation.
    Mol Cell Biol. 2000 Jan;20(1):312-8 PMID: 10594033
  14. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.
    Nat Genet. 2005 Apr;37(4):391-400 PMID: 15765097
  15. Involvement of human MOF in ATM function.
    Mol Cell Biol. 2005 Jun;25(12):5292-305 PMID: 15923642
  16. ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets.
    Dev Biol. 2003 Apr 1;256(1):73-88 PMID: 12654293
  17. Acetylation of histones and transcription-related factors.
    Microbiol Mol Biol Rev. 2000 Jun;64(2):435-59 PMID: 10839822
  18. Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities.
    Endocrinology. 2007 Aug;148(8):3987-97 PMID: 17495001
  19. Specific association of human telomerase activity with immortal cells and cancer.
    Science. 1994 Dec 23;266(5193):2011-5 PMID: 7605428
  20. Histone H4 lysine 16 acetylation breaks the genome's silence.
    Genome Biol. 2006;7(5):217 PMID: 16689998
  21. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span.
    Curr Biol. 1998 Feb 26;8(5):279-82 PMID: 9501072
  22. Initial chromosome damage but not DNA damage is greater in ataxia telangiectasia cells.
    Radiat Res. 1992 Apr;130(1):94-103 PMID: 1561323
  23. Extension of life-span by introduction of telomerase into normal human cells.
    Science. 1998 Jan 16;279(5349):349-52 PMID: 9454332
  24. Meiotic telomere distribution and Sertoli cell nuclear architecture are altered in Atm- and Atm-p53-deficient mice.
    Mol Cell Biol. 2000 Oct;20(20):7773-83 PMID: 11003672
  25. Human heterochromatin protein 1 isoforms HP1(Hsalpha) and HP1(Hsbeta) interfere with hTERT-telomere interactions and correlate with changes in cell growth and response to ionizing radiation.
    Mol Cell Biol. 2003 Nov;23(22):8363-76 PMID: 14585993
  26. mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila.
    EMBO J. 1997 Apr 15;16(8):2054-60 PMID: 9155031
  27. Spontaneously immortalized cell lines obtained from adult Atm null mice retain sensitivity to ionizing radiation and exhibit a mutational pattern suggestive of oxidative stress.
    Oncogene. 2001 Jul 19;20(32):4291-7 PMID: 11466609
  28. Neoplastic transformation of mouse C3H10T1/2 cells following exposure to neutrons does not involve mutation of ras gene as analyzed by SSCP and cycle sequencing.
    Mutat Res. 1996 Oct 25;357(1-2):237-44 PMID: 8876700
  29. Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression.
    Oncogene. 2001 Jan 18;20(3):278-88 PMID: 11313956
  30. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation.
    PLoS Genet. 2006 Mar;2(3):e40 PMID: 16596166
  31. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16.
    Mol Cell Biol. 2005 Nov;25(21):9175-88 PMID: 16227571
  32. ATM and related protein kinases: safeguarding genome integrity.
    Nat Rev Cancer. 2003 Mar;3(3):155-68 PMID: 12612651
  33. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress.
    Cell Metab. 2005 Jul;2(1):67-76 PMID: 16054100
  34. Telomerase activity as a measure for monitoring radiocurability of tumor cells.
    FASEB J. 1999 Jun;13(9):1047-54 PMID: 10336887
  35. Ionizing radiation activates the ATM kinase throughout the cell cycle.
    Oncogene. 2000 Mar 9;19(11):1386-91 PMID: 10723129
  36. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF.
    Cell. 2005 Jun 17;121(6):873-85 PMID: 15960975
  37. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells.
    Mol Cell Biol. 2005 Aug;25(15):6798-810 PMID: 16024812
  38. Acetylation of the p53 DNA-binding domain regulates apoptosis induction.
    Mol Cell. 2006 Dec 28;24(6):841-51 PMID: 17189187
  39. Role of mammalian Rad9 in genomic stability and ionizing radiation response.
    Cell Cycle. 2006 Jun;5(12):1289-91 PMID: 16760671
  40. Genome maintenance mechanisms for preventing cancer.
    Nature. 2001 May 17;411(6835):366-74 PMID: 11357144
  41. Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia.
    Hum Mol Genet. 2005 Oct 1;14(19):2929-43 PMID: 16150740
  42. Genomic instability and enhanced radiosensitivity in Hsp70.1- and Hsp70.3-deficient mice.
    Mol Cell Biol. 2004 Jan;24(2):899-911 PMID: 14701760
  43. Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair.
    Nature. 2002 Sep 26;419(6905):411-5 PMID: 12353039
  44. Quantitative and qualitative studies of chemical transformation of cloned C3H mouse embryo cells sensitive to postconfluence inhibition of cell division.
    Cancer Res. 1973 Dec;33(12):3239-49 PMID: 4796800
  45. Influence of ATM function on telomere metabolism.
    Oncogene. 1997 Nov 27;15(22):2659-65 PMID: 9400992
  46. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin.
    Nat Genet. 2002 Nov;32(3):378-83 PMID: 12379856
  47. Assessment of the mutagenic potential of a fungicide Bavistin using multiple assays.
    Mutat Res. 1988 Apr;204(4):627-43 PMID: 3280996
  48. Mutagenic studies on the insecticide Metasystox-R with different genetic systems.
    Mutat Res. 1983 Oct;124(1):97-102 PMID: 6415477
  49. Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila.
    Genes Dev. 1994 Jan;8(1):96-104 PMID: 8288132
  50. Histone H4 acetylation distinguishes coding regions of the human genome from heterochromatin in a differentiation-dependent but transcription-independent manner.
    EMBO J. 1995 Aug 15;14(16):3946-57 PMID: 7664735
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.01045-07
Published
2008-01-00
Epub
2007-00-29
Pages
397-409
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2223300
Subset
IM
Grants
NCI NIH HHS · P01 CA097403 · United States
NCI NIH HHS · CA10445 · United States
NCI NIH HHS · CA123232 · United States
NCI NIH HHS · R01 CA123232 · United States
NCI NIH HHS · P01 CA97403 · United States
External Links
PubMed source DOI: 10.1128/MCB.01045-07 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2