The Department of Molecular and Cellular Biochemistry




Mark R. Parthun

Associate Professor

Ph.D. - Indiana University

Post Doctoral - Northwestern University, Fred Hutchinson Cancer Research Center

The DNA of eukaryotic cells is packaged in a nucleoprotein complex known as chromatin. The fundamental unit of chromatin is the nucleosome, which consists of approximately two turns of DNA wrapped around a protein core of histones H2A, H2B, H3 and H4. The core histones are important not only for the structural packaging of DNA in the nucleus but also for regulating many cellular processes that use DNA as a substrate. The proper control of these processes, which include transcription, replication, recombination and DNA repair, is essential for maintaining cellular growth control.

Much of the regulatory potential of the histones lies in their NH2-termini. The NH2-terminal tails, the first ~30 amino acids of each histone, are largely unstructured and contain high concentrations of lysine and arginine residues. These domains appear to project out from the nucleosome structure and, as such, are in a position to make contacts with both the DNA as it wraps around the histone octamer and with chromatin associated proteins. An intriguing characteristic of the NH2-terminal tails is that their physical properties are regulated by extensive post-translational modifications, which include phosphorylation, methylation, ubiquitination, ADP-ribosylation, and acetylation.

Acetylation of core histone NH2-terminal tails was discovered more than 30 years ago and has been the most extensively studied histone modification. Histone acetylation occurs on lysine residues, neutralizing their positive charge and changing their structure. As such, this modification is likely to affect the interaction of histones with both DNA and other proteins. The acetylation of the core histones is a dynamic process, with the acetylation state of a given histone determined by the actions of enzymes that add acetyl groups (histone acetyltransferases) and enzymes that remove them (histone deacetylases).

Our laboratory is focused on the type B histone acetyltransferases. This class of enzymes is localized to the cytoplasm and specifically acetylates free histones. These enzymes are thought to acetylate newly synthesized histones during the process of chromatin assembly. Using both biochemical and genetic methods we are currently characterizing the in vivo role of this intriguing, evolutionarily conserved, enzyme family.

 

Recent Publications:

Parthun MR (2007) "Hat1: the emerging cellular roles of a type B histone acetyltransferase" Oncogene. 26(37):5319-28.

Knapp AR, Ren C, Su X, Lucas DM, Byrd JC, Freitas MA and Parthun MR (2007)"Quantitative profiling of histone post-translational modifications by stable isotope labeling" Methods 41(3):312-9.

Su X, Zhang L, Lucas DM, Davis ME, Knapp AR, Green-Church KB, Marcucci G, Parthun MR, Byrd JC and Freitas MA (2007) "Histone H4 acetylation dynamics determined by stable isotope labeling with amino acids in cell culture and mass spectrometry" Anal Biochem 363(1):22-34.

Su X, Jacob NK, Amunugama R, Lucas DM, Knapp AR, Ren C, Davis ME, Marcucci G, Parthun MR, Byrd JC, Fishel R and Freitas MA (2007)"Liquid chromatography mass spectrometry profiling of histones" J Chromatogr B Analyt Technol Biomed Life Sci 850(1-2):440-54.

Zhang L, Su X, Liu S, Knapp AR, Parthun MR, Marcucci G and Freitas MA (2006) "Histone H4 N-terminal acetylation in Kasumi-1 cells treated with depsipeptide determined by acetic acid-urea polyacrylamide gel electrophoresis, amino acid coded mass tagging, and mass spectrometry" J Proteome Res 6(1):81-8.

Mersfelder EL and Parthun MR (2006) "The tale beyond the tail: histone core domain modifications and the regulation of chromatin structure" Nucleic Acids Res 34(9):2653-62.

Lindstrom JC, Vary Jr, JC, Parthun MR, Delrow J and Tsukiyama T (2006) "Isw1 functions in parallel with the NuA4 and Swr1 complexes in stress-induced gene repression" Mol Cell Biol 26:6117-29.

Qin S and Parthun MR (2006) "Recruitment of the type B histone acetyltransferase Hat1p to chromatin is linked to DNA double-stran breaks" Mol Cell Biol 26(9):3649-58.

Ren C, Ghoshal K, Zhang L, Parthun MR, Jacob ST and Freitas MA (2005) "Peptide mass mapping of acetylated isoforms of histone H4 from mouse lymphosarcoma cells treated with histone deacetylase (HDACs) inhibitors" J Am Soc Mass Spec 16(20):1641-53.

Ye J, Ai X, Eugenie E, Zhang L, Carpenter LR, Jelinek MA, Freitas MA and Parthun MR (2005) "Histone H4 lysine 91 acetylation: a core domain modification associated with chromatin assembly" Mol Cell 18:123-30.

Byrd JC, Marcucci G, Parthun MR, Xiu JJ, Bruner R, Moran M, Lin TS, Liu S, Wickham J, Davis M, Lucas D, Fischer B, Shank R, Binkley P, Wright J, Chan K and Grever MR (2005) "A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia" Blood 105(3):959-67.

Ai X and Parthun MR (2004) "The nuclear Hat1p/Hat2p complex: a molecular link between type B histone acetyltransferases and chromatin assembly" Mol Cell 14:195-205.

Aron JL, Parthun MR, Marcucci G, Kitada S, Mone AP, Davis ME, Shen T, Murphy T, Wickham J, Kanakry C, Lucas DM, Reed JC, Grever MR and Byrd JC (2003) "Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase-8 mediated apoptosis and down regulation of c-FLIP protein" Blood 102:652-58.

Qin S and Parthun MR (2002) "Histone H3 and the histone acetyltransferase Hat1p contribute to DNA double strand break repair" Mol Cell Biol 22:8353-65.

Kelly T, Qin S, Gottschling DE and Parthun MR (2000) "Type B histone acetyltransferase Hat1p participates in telomeric silencing" Mol Cell Biol 20:7051-58.

Parthun MR, Widom J and Gottschling D (1996) "The major cytoplasmic histone acetyltransferase in yeast: links to chromatin replication and histone metabolism" Cell 87:85-94.

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Last Modified: 10/10/07