H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication.
DNA replication is tightly regulated to occur once and only once per cell cycle. How chromatin, the physiological substrate of DNA replication machinery, regulates DNA replication remains largely unknown. Here we show that histone H3 lysine 9 demethylase Kdm4d regulates DNA replication in eukaryotic cells. Depletion of Kdm4d results in defects in DNA replication, which can be rescued by the expression of H3K9M, a histone H3 mutant transgene that reverses the effect of Kdm4d on H3K9 methylation. Kdm4d interacts with replication proteins, and its recruitment to DNA replication origins depends on the two pre-replicative complex components (origin recognition complex [ORC] and minichromosome maintenance [MCM] complex). Depletion of Kdm4d impairs the recruitment of Cdc45, proliferating cell nuclear antigen (PCNA), and polymerase δ, but not ORC and MCM proteins. These results demonstrate a novel mechanism by which Kdm4d regulates DNA replication by reducing the H3K9me3 level to facilitate formation of pre-initiative complex.
Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN 55902, USA.
Rentian
R
Wu
Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN 55902, USA.
Zhiquan
Z
Wang
Institute for Cancer Genetics, Department of Pediatric and Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Honglian
H
Zhang
Institute for Cancer Genetics, Department of Pediatric and Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Haiyun
H
Gan
Institute for Cancer Genetics, Department of Pediatric and Department of Genetics and Development, Columbia University, New York, NY 10032, USA zz2401@cumc.columbia.edu.
Zhiguo
Z
Zhang
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D045325:HCT116 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D064148:Minichromosome Maintenance Complex Component 4 / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
C113571:CDC45 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D034921:Lamin Type B; C489427:MYC protein, human; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D056484:Jumonji Domain-Containing Histone Demethylases; C521694:KDM4D protein, human; D004258:DNA Polymerase III; C099243:MCM4 protein, human; D064148:Minichromosome Maintenance Complex Component 4
Nat Struct Mol Biol. 2013 Apr;20(4):412-8
23552296
Science. 2013 May 24;340(6135):981-4
23704573
Nat Protoc. 2013 Mar;8(3):602-26
23449254
J Cell Biochem. 2005 May 1;95(1):74-82
15723284
J Biol Chem. 2004 May 7;279(19):20067-75
14982920
Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):E728-37
24550317
Nat Cell Biol. 2010 Nov;12(11):1086-93
20953199
Nat Cell Biol. 2006 Apr;8(4):358-66
16531994
Cell Cycle. 2012 Apr 1;11(7):1325-39
22421151
Nature. 2010 Aug 19;466(7309):987-91
20631708
J Biol Chem. 2011 Dec 2;286(48):41616-25
21914792
PLoS Comput Biol. 2013;9(10):e1003233
24130466
Nucleic Acids Res. 2015 Mar 11;43(5):2560-74
25712104
Nat Protoc. 2011 Jun;6(6):870-95
21637205
Science. 2014 Mar 14;343(6176):1249-53
24626927
Nat Commun. 2016 Jan 11;7:10208
26751768
Nature. 2012 Mar 07;484(7392):115-9
22398447
EMBO J. 2012 Apr 18;31(8):1865-78
22373579
J Biol Chem. 2008 Apr 25;283(17):11073-7
18319261
Nucleic Acids Res. 2012 Jan;40(1):159-69
21908399
Nature. 2011 Aug 03;478(7370):524-8
21814200
Science. 2013 May 17;340(6134):857-61
23539183
Mol Cell. 2010 Jan 15;37(1):57-66
20129055
Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16699-704
21940502
J Cell Biol. 2006 Jul 17;174(2):185-94
16831888
Genes Dev. 2010 Mar 15;24(6):602-12
20231317
Mol Cell. 2013 Jul 11;51(1):80-91
23849629
Cancer Res. 2013 May 15;73(10):2936-42
23644528
J Biol Chem. 2013 Jul 19;288(29):21376-88
23744078
Genes Dev. 2013 May 1;27(9):985-90
23603901
Cell Cycle. 2002 Nov-Dec;1(6):416-23
12548018
Cell. 2011 Dec 23;147(7):1628-39
22196736
J Biol Chem. 2012 Apr 27;287(18):15024-33
22427655
Genome Res. 2010 Jun;20(6):771-80
20435908
Genome Res. 2011 Nov;21(11):1822-32
21813623
Genes Dev. 2012 Dec 1;26(23 ):2580-9
23152447
Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):E4810-9
27436900
Nat Rev Genet. 2014 Apr;15(4):272-86
24614317
Cell. 2007 Feb 23;128(4):721-33
17320509
Mol Cell. 2011 Dec 23;44(6):966-77
22195969
Genes Dev. 2008 Oct 1;22(19):2633-8
18832067
Cell Cycle. 2015;14(7):950-8
25714495
Annu Rev Biochem. 2013;82:25-54
23746253
Chromosome Res. 2010 Jan;18(1):115-25
20205353
Cell. 2013 Aug 1;154(3):541-55
23871696
Mol Biol Cell. 2005 Jun;16(6):2872-81
15788566
Structure. 2013 Jan 8;21(1):98-108
23219879
Mol Cell. 2010 Dec 10;40(5):736-48
21145482
Cold Spring Harb Perspect Biol. 2013 Jul 01;5(7):null
23818497
Epigenetics. 2011 Jan;6(1):9-15
20855937
Mol Cell. 2014 Jul 17;55(2):277-90
24981170
Nucleic Acids Res. 2012 Apr;40(7):3208-17
22140117
PLoS Genet. 2014 May 01;10(5):e1004282
24785686
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1692-7
18234858
Hum Mol Genet. 2009 Oct 15;18(R2):R195-201
19808796