CST Guide:

Section I: Research Areas
chapter 01: GENE EXPRESSION, EPIGENETICS, AND NUCLEAR FUNCTION
References
61. Fernandez-Capetillo, O. et al.
(2004) J. Exp. Med. 199,
1671–1677.
62. Maile, T. et al. (2004)
Science 304, 1010–1014.
63. Dai, J. et al. (2004)
Genes Dev. 19, 472–488.
64. Hendzel, M.J. et al. (1997)
Chromosoma 106, 348–360.
65. Hsu, J.Y. et al. (2000)
Cell 102, 279–291.
66. Soloaga, A. et al. (2003)
EMBO J. 22, 2788–2797.
67. Anest, V. et al. (2003)
Nature 423, 659–663.
68. Lo, W.S. et al. (2001)
Science 293, 1142–1146.
69. Preuss, U. et al. (2003) Nucleic
Acids Res. 31, 878–885.
70. Goto, H. et al. (2002)
Genes Cells 7, 11–17.
71. Zhong, S. et al. (2001) J. Biol.
Chem. 276, 33213–33219.
72. Cheung, W.L. et al. (2005)
Curr. Biol. 15, 656–660.
73. Wang, H. et al. (2004)
Nature 431, 873–878.
74. Zhu, B. et al. (2005)
Mol. Cell. 20, 601–611.
75. Robzyk, K. et al. (2000)
Science 287, 501–504.
76. Nathan, D. et al. (2006)
Genes Dev. 20, 966–976.
77. Shiio, Y. and Eisenman, R.N.
(2003) Proc. Natl. Acad. Sci.
USA 100, 13225–13230.
78. Chew, Y.C. et al. (2006) J.
Nutr. Biochem. 17, 225–233.
79. Kobza, K. et al. (2005)
FEBS J. 272, 4249–4259.
80. Camporeale, G. et al. (2004)
Eur. J. Biochem. 271,
2257–2263.
81. Kothapalli, N. and Zempleni, J.
(2004) FASEB J. 18, 103–104.
82. Morris, S.A. et al. (2007) J.
Biol Chem. 282, 7632–7640.
83. DiLorenzo, A. et al. (2011)
FEBS Lett. 585, 2024–2031.
84. Bungard, D. et al. (2010)
Science 329, 1201–1205.
85. Metzger, E. et al. (2010)
Nature 464, 792–796.
86. Dawson, M.A. et al. (2009)
Nature 461, 819–822.
87. Hurd, P.J. et al. (2009) J. Biol.
Chem. 284, 16575–16583.
88. Su, X. et al. (2014)
Genes Dev. 28, 622–636.
89. Casadio, F. et al. (2013)
Proc. Natl. Acad. Sci. USA
110, 14894–14899.
90. Yamagishi, Y. et al. (2010)
Science 330, 239–243.
91. Kim, K. et al. (2013)
Mol. Cell 52, 459–467.
92. Xiao, A. et al. (2009)
Nature 457, 57–62.
Phosphorylation
Histone Site Histone-modifying Enzymes Proposed Function Ref. #
H1 Ser27
transcriptional activation, chromatin
unknown
(48,49)
decondensation
H2A Ser1 unknown mitosis, chromatin assembly (50)
MSK1 transcriptional repression (51)
Ser122 (S. cerevisiae) unknown DNA repair (53)
Ser129 (S. cerevisiae) Mec1, Tel1 DNA repair (54,55)
Ser139 (mammalian H2A.X) ATR, ATM, DNA-PK DNA repair (56-58)
Thr119 (D. melanogaster) NHK1 mitosis (52)
Thr120 (mammals) Bub1, VprBP mitosis, transcriptional repression (90,91)
Thr142 (mammalian H2A.X) WSTF apoptosis, DNA repair (92)
H2B Ser10 (S. cerevisiae) Ste20 apoptosis (59)
Ser14 (vertebrates) Mst1 apoptosis (60)
unknown DNA repair (61)
Ser33 (D. melanogaster) TAF1 transcriptional activation (62)
Ser36 AMPK transcriptional activation (84)
H3 Ser10 Aurora-B kinase mitosis, meiosis (64,65)
MSK1, MSK2 immediate-early gene activation (66)
IKK-α transcriptional activation (67)
Snf1 transcriptional activation (68)
Ser28 (mammals) Aurora-B kinase mitosis (70)
MSK1, MSK2 immediate-early activation (66,71)
Thr3 Haspin/Gsg2 mitosis (63)
Thr6 PKCbI (85)
Thr11 (mammals) Dlk/Zip mitosis (69)
Tyr41 JAK2 transcriptional activation (86)
Tyr45 PKCd apoptosis (87)
H4 Ser1 unknown mitosis, chromatin assembly (50)
CK2 DNA repair (72)
Ubiquitination
Histone Site Histone-modifying Enzymes Proposed Function Ref. #
H2A Lys119 (mammals) Ring2 spermatogenesis (73)
H2B Lys120 (mammals) UbcH6 meiosis (74)
Lys123 (S. cerevisiae)
transcriptional activation
Rad6
(75)
euchromatin
Sumoylation
Histone Site Histone-modifying Enzymes Proposed Function Ref. #
H2A Lys126 (S. cerevisiae) Ubc9 transcriptional repression (76)
H2B Lys6 or Lys7 (S. cerevisiae) Ubc9 transcriptional repression (76)
H4 N-terminal tail (S. cerevisiae) Ubc9 transcriptional repression (77)
Biotinylation
Histone Site Histone-modifying Enzymes Proposed Function Ref. #
H2A Lys9 biotinidase unknown (78)
Lys13 biotinidase unknown (78)
H3 Lys4 biotinidase gene expression (79)
Lys9 biotinidase gene expression (79)
Lys18 biotinidase gene expression (79)
H4 Lys12 biotinidase DNA damage response (80,81)
Examples of Crosstalk Between Post-Translational Modifications
Histone H3
Histone H3 and H4
p53
MEF2A
Transcriptional
Repression
Pim-1
S10
H3
14-3-3
HP1
S10
Me
K9
H3
MOF
K14
Resting Neurons
PIAS1
K403 Su S408
MEF2A
K16
HP1
dissociation
P-TEFb
BRD4
HATs
HP1
DNA Damage
Aurora B, Ras
H3
GCN5
Membrane Depolarization
Calcineurin
Transcription
Transcriptional
Activation
Chk2 Set7/9
MDM2
TIP60
Ub K372
K120
K372
dissociation
Me
S20
Me K372
MDM2
Ub K373
S20
CBP/
p53 p53 p53 K381 p300
Ub K381
Ub K382
K382
p53 Ubiquitination/Degradation
p53 Stability/Transactivation of
pro-apoptotic target genes
Dendric Claw
Differentiation
Transcriptional Repression
H4
S10
K9
H3
K9
S10
K403 S408
MEF2A
K14
K14
RNA Pol II
No Differentiation
Transcriptional Activation
Post-translational modifications (PTMs) are emerging as major effectors of protein function, and in turn, cellular processes. The discovery and investigation of post-translational
modifications such as methylation, acetylation, phosphorylation, sumoylation, and many others has established both nuclear and non-nuclear roles for PTMs. With the
awareness of PTMs, there is an ever-growing list of them and more and more research centered on their function. In recent years, there is an overwhelming appreciation for
the diversity of modifications, but most importantly, the interplay between them. This interplay is essential for proper gene expression, genome organization, cell division and
DNA damage response. PTMs can directly impact cell function by modifying histones, modifying enzymes and their associated activity, assembling protein complexes as well
as recognition and targeting in the genome or to other cellular compartments. In the context of single modifications and gene expression, acetylation of certain lysines (i.e.,
Histone 3 lysine [9-H3K9]) correlates with activation, while tri-methylation of this same residue is most often associated with compaction and gene repression. In the case of
lysine methylation, lysine can be mono-, di-, or tri-methylated; while arginine can be mono- or dimethylated in an asymmetric or symmetric fashion. Each degree of methylation
for lysines and arginines serves as its own PTM and impacts biological output. Most PTMs do not exist alone in the chromatin environment and the combination of these
states can reinforce one another. For example, one PTM can serve as a docking site for a binding domain called a “reader” within one protein, while another “reader” within
the same protein can recognize another residue. This is the case for the reader protein BPTF, which binds both H3K4me3 and H4K16 acetylation. Therefore, modulating the
various types and degrees of modifications will impact output. For these reasons, the cell has developed a series of enzymes that are important for establishing and maintaining
these PTMs, which are often referred to as “writers” (e.g., histone methyltransferases, acetyltransferases, etc.) or “erasers” (e.g., histone demethylases, deacetylases,
etc.). Many of these enzymes have emerged as critical therapeutic targets and have been identified as key regulators of diseases such as cancer. These observations have
also made their associated PTMs candidates for biomarkers in cancer and other diseases.
Select Reviews:
Berger, S.L. (2007) Nature 447, 407–412. • Dawson, M.A., and Kouzarides T. (2012) Cell 150, 12–27. • Gardner, K.E., Allis, C.D., and Strahl, B.D. (2011) J. Mol. Biol.
409, 36–46. • Lee, J.S., Smith, E., and Shilatifard, A. (2010) Cell 142, 682–685. • Musselman, C.A. and Kutateladze, T.G. (2011) Acids Res. 39, 9061–9071. • Yang,
X.J. and Seto, E. (2008) Mol. Cell 31, 449–461.
Ca +2
© 2006–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. Jonathan Whetstine for reviewing this diagram.
30 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.
www.cellsignal.com/cstpathways 31