PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.
PTIP, a protein with tandem BRCT domains, has been implicated in DNA damage response. However, its normal cellular functions remain unclear. Here we show that while ectopically expressed PTIP is capable of interacting with DNA damage response proteins including 53BP1, endogenous PTIP, and a novel protein PA1 are both components of a Set1-like histone methyltransferase (HMT) complex that also contains ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, SET domain-containing HMTs MLL3 and MLL4, and substoichiometric amount of JmjC domain-containing putative histone demethylase UTX. PTIP complex carries robust HMT activity and specifically methylates lysine 4 (K4) on histone H3. Furthermore, PA1 binds PTIP directly and requires PTIP for interaction with the rest of the complex. Moreover, we show that hDPY-30 binds ASH2L directly. The evolutionarily conserved hDPY-30, ASH2L, RBBP5, and WDR5 likely constitute a subcomplex that is shared by all human Set1-like HMT complexes. In contrast, PTIP, PA1, and UTX specifically associate with the PTIP complex. Thus, in cells without DNA damage agent treatment, the endogenous PTIP associates with a Set1-like HMT complex of unique subunit composition. As histone H3 K4 methylation associates with active genes, our study suggests a potential role of PTIP in the regulation of gene expression.
Cho
Young-Wook
YW
Nuclear Receptor Biology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hong
Teresa
T
Hong
Sunhwa
S
Guo
Hong
H
Yu
Hong
H
Kim
Doyeob
D
Guszczynski
Tad
T
Dressler
Gregory R
GR
Copeland
Terry D
TD
Kalkum
Markus
M
Ge
Kai
K
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011496:Protein Methyltransferases; D011499:Protein Processing, Post-Translational / Q000502:physiology*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; C452979:KMT2C protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C485876:PAXIP1 protein, human; C412792:Paxip1 protein, mouse; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C510652:Kmt2c protein, mouse; C516439:MLL4 protein, mouse; D008239:Lysine