title: Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication.
abstract: The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints.
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Piunti
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rossi
authors.affiliation: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Cerutti
authors.affiliation: 1] Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark [2] Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Mareike
authors.initials: M
authors.lastname: Albert
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy.
authors.forename: Sriganesh
authors.initials: S
authors.lastname: Jammula
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scelfo
authors.affiliation: 1] European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy [2] Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cedrone
authors.affiliation: 1] European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy [2] IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fragola
authors.affiliation: 1] Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark [2] Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Linda
authors.initials: L
authors.lastname: Olsson
authors.affiliation: Developmental Genetics Group, RIKEN Research Center for Allergy & Immunology (RCAI), 1-7-22 Suehiuro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Testa
authors.affiliation: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Casola
authors.affiliation: 1] Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark [2] Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark [3] The Danish Stem Cell Centre, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.affiliation: 1] IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy [2] Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia 27100, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Pasini
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D020552:Comet Assay; D004261:DNA Replication / Q000502:physiology*; D005260:Female; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D063146:Polycomb-Group Proteins
references.citation: Nat Cell Biol. 2003 Aug;5(8):741-7
references.pmid: 12855956
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Cancer Res. 2008 Aug 15;68(16):6507-15
references.pmid: 18701473
references.citation: Genes Dev. 2009 Apr 15;23(8):975-85
references.pmid: 19390090
references.citation: Mol Cell. 2004 Jul 2;15(1):57-67
references.pmid: 15225548
references.citation: Oncogene. 2013 Aug 1;32(31):3616-26
references.pmid: 22907436
references.citation: Brief Funct Genomic Proteomic. 2003 Jan;1(4):385-96
references.pmid: 15239885
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5
references.pmid: 23236167
references.citation: Pathol Int. 2004 Nov;54(11):811-8
references.pmid: 15533223
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e12
references.pmid: 12582257
references.citation: Nat Immunol. 2003 Feb;4(2):124-31
references.pmid: 12496962
references.citation: EMBO J. 2007 Mar 21;26(6):1637-48
references.pmid: 17332741
references.citation: Nature. 2006 Nov 30;444(7119):638-42
references.pmid: 17136094
references.citation: Nat Cell Biol. 2011 Mar;13(3):243-53
references.pmid: 21317883
references.citation: Nature. 2007 Feb 8;445(7128):661-5
references.pmid: 17251932
references.citation: Oncogene. 2012 May 24;31(21):2601-13
references.pmid: 21963855
references.citation: Dev Cell. 2004 Nov;7(5):663-76
references.pmid: 15525528
references.citation: Genes Dev. 2012 Mar 1;26(5):439-44
references.pmid: 22391448
references.citation: Biotechniques. 2013 Oct;55(4):204-6
references.pmid: 24107252
references.citation: Nature. 2012 Dec 6;492(7427):108-12
references.pmid: 23051747
references.citation: Future Oncol. 2011 Jan;7(1):57-75
references.pmid: 21174538
references.citation: Mol Cell. 2013 Feb 21;49(4):645-56
references.pmid: 23352454
references.citation: Nat Cell Biol. 2013 Apr;15(4):348-50
references.pmid: 23548929
references.citation: Cancer Res. 2012 Feb 1;72(3):626-35
references.pmid: 22298595
references.citation: Carcinogenesis. 2000 May;21(5):865-9
references.pmid: 10783305
references.citation: Genes Dev. 2005 Jun 15;19(12):1438-43
references.pmid: 15964995
references.citation: Nature. 1999 Jul 29;400(6743):464-8
references.pmid: 10440377
references.citation: Nature. 2007 Aug 2;448(7153):553-60
references.pmid: 17603471
references.citation: Nature. 2011 Jan 20;469(7330):343-9
references.pmid: 21248841
references.citation: Immunity. 2008 Feb;28(2):231-45
references.pmid: 18275833
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5389-94
references.pmid: 17374722
references.citation: Cancer Res. 2007 Nov 1;67(21):10286-95
references.pmid: 17974970
references.citation: Nat Cell Biol. 2010 Oct;12(10):982-92
references.pmid: 20818389
references.citation: Cell. 2009 Apr 17;137(2):247-58
references.pmid: 19361851
references.citation: Nat Chem Biol. 2012 Nov;8(11):890-6
references.pmid: 23023262
references.citation: Nat Cell Biol. 2004 Jan;6(1):67-72
references.pmid: 14647293
references.citation: Mol Cell. 2003 Aug;12(2):393-400
references.pmid: 14536079
references.citation: Cell. 1996 Apr 5;85(1):27-37
references.pmid: 8620534
references.citation: Mol Cell Biol. 1999 Aug;19(8):5339-51
references.pmid: 10409725
references.citation: Leukemia. 2004 Jan;18(1):146-55
references.pmid: 14603341
references.citation: Methods. 2012 Jun;57(2):149-57
references.pmid: 22579803
references.citation: Nat Cell Biol. 2010 Jan;12(1):54-9; sup pp 1-14
references.pmid: 20010815
references.citation: J Clin Invest. 2012 May;122(5):1920-32
references.pmid: 22505453
references.citation: Cell. 2009 Apr 3;137(1):110-22
references.pmid: 19303136
references.citation: Genes Dev. 2007 Mar 1;21(5):525-30
references.pmid: 17344414
references.citation: Oncogene. 2014 Jan 23;33(4):421-8
references.pmid: 23318437
references.citation: Cell. 1997 Nov 28;91(5):649-59
references.pmid: 9393858
references.citation: Cell. 2006 Oct 20;127(2):265-75
references.pmid: 17055429
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1720-5
references.pmid: 23319651
references.citation: J Biol Chem. 2012 Oct 19;287(43):35784-94
references.pmid: 22910904
references.citation: Nat Rev Mol Cell Biol. 2012 Sep;13(9):579-90
references.pmid: 22914294
references.citation: Nat Cell Biol. 2008 Nov;10(11):1291-300
references.pmid: 18931660
references.citation: Genes Dev. 1999 Oct 15;13(20):2678-90
references.pmid: 10541554
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):667-77
references.pmid: 16921403
references.citation: Nat Struct Mol Biol. 2013 Nov;20(11):1250-7
references.pmid: 24077223
references.citation: Science. 1997 Sep 5;277(5331):1518-23
references.pmid: 9278517
references.citation: Nat Commun. 2012 May 08;3:815
references.pmid: 22569363
references.citation: Nature. 1999 Jan 14;397(6715):164-8
references.pmid: 9923679
references.citation: Cell. 2007 May 18;129(4):665-79
references.pmid: 17512402
references.citation: Genes Dev. 2009 Apr 15;23(8):906-11
references.pmid: 19390085
references.citation: Mol Cell Biol. 2007 May;27(10):3769-79
references.pmid: 17339329
references.citation: EMBO J. 2004 Oct 13;23(20):4061-71
references.pmid: 15385962
references.citation: Cancer Cell. 2007 Oct;12(4):328-41
references.pmid: 17936558
references.citation: Nat Rev Cancer. 2009 Jun;9(6):441-4
references.pmid: 19461668