title: Persistent replicative stress alters polycomb phenotypes and tissue homeostasis in Drosophila melanogaster.
abstract: Polycomb group (PcG) proteins establish and maintain genetic programs that regulate cell-fate decisions. Drosophila multi sex combs (mxc) was categorized as a PcG gene based on a classical Polycomb phenotype and genetic interactions; however, a mechanistic connection between Polycomb and Mxc has not been elucidated. Hypomorphic alleles of mxc are characterized by male and female sterility and ectopic sex combs. Mxc is an important regulator of histone synthesis, and we find that increased levels of the core histone H3 in mxc mutants result in replicative stress and a persistent DNA damage response (DDR). Germline loss, ectopic sex combs and the DDR are suppressed by reducing H3 in mxc mutants. Conversely, mxc phenotypes are enhanced when the DDR is abrogated. Importantly, replicative stress induced by hydroxyurea treatment recapitulated mxc germline phenotypes. These data reveal how persistent replicative stress affects gene expression, tissue homeostasis, and maintenance of cellular identity in vivo.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Severine
authors.initials: S
authors.lastname: Landais
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: D'Alterio
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: leannejones@ucla.edu.
authors.forename: D Leanne
authors.initials: DL
authors.lastname: Jones
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D005260:Female; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006918:Hydroxyurea / Q000494:pharmacology; D008297:Male; D010641:Phenotype; D010766:Phosphorylation; D063146:Polycomb-Group Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013737:Testis / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D006657:Histones; C000604521:Mxc protein, Drosophila; D063146:Polycomb-Group Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D006918:Hydroxyurea
references.citation: J Cell Physiol. 2010 Feb;222(2):456-64
references.pmid: 19890848
references.citation: Cell Stem Cell. 2010 Sep 3;7(3):299-313
references.pmid: 20804967
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):470-8
references.pmid: 18371382
references.citation: Development. 1993 Apr;117(4):1223-37
references.pmid: 8404527
references.citation: Science. 2001 Dec 21;294(5551):2542-5
references.pmid: 11752574
references.citation: Dev Cell. 2013 Mar 25;24(6):623-34
references.pmid: 23537633
references.citation: Genes Dev. 2001 Apr 15;15(8):1021-30
references.pmid: 11316795
references.citation: Nature. 1999 Jun 17;399(6737):694-7
references.pmid: 10385122
references.citation: Science. 2005 Nov 4;310(5749):869-72
references.pmid: 16272126
references.citation: Mol Cell. 2002 Jun;9(6):1191-200
references.pmid: 12086617
references.citation: Nature. 2010 May 13;465(7295):243-7
references.pmid: 20436459
references.citation: J Cell Biol. 2011 May 16;193(4):677-94
references.pmid: 21576393
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16964-9
references.pmid: 18957539
references.citation: PLoS One. 2012;7(12):e52892
references.pmid: 23285219
references.citation: Mech Dev. 2000 Mar 1;91(1-2):451-4
references.pmid: 10704882
references.citation: Cell. 2003 Nov 26;115(5):537-49
references.pmid: 14651846
references.citation: Curr Opin Cell Biol. 2002 Dec;14(6):692-9
references.pmid: 12473341
references.citation: Genes Dev. 2005 Jan 1;19(1):65-76
references.pmid: 15630020
references.citation: Rouxs Arch Dev Biol. 1996 Feb;205(5-6):203-214
references.pmid: 28306023
references.citation: Nucleic Acids Res. 2002 Sep 1;30(17):3698-705
references.pmid: 12202754
references.citation: Cell Cycle. 2010 Oct 15;9(20):4236-44
references.pmid: 20948314
references.citation: Science. 2013 May 17;340(6134):857-61
references.pmid: 23539183
references.citation: Genetics. 1998 Aug;149(4):1823-38
references.pmid: 9691040
references.citation: Nature. 1978 Dec 7;276(5688):565-70
references.pmid: 103000
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5284-9
references.pmid: 21402923
references.citation: Nat Rev Cancer. 2006 Nov;6(11):846-56
references.pmid: 17060944
references.citation: Nat Rev Genet. 2007 Jan;8(1):9-22
references.pmid: 17173055
references.citation: Mol Gen Genet. 1995 Feb 6;246(3):282-90
references.pmid: 7854313
references.citation: EMBO J. 2011 May 18;30(10):2008-18
references.pmid: 21487390
references.citation: Nat Cell Biol. 2010 Aug;12(8):806-11
references.pmid: 20622868
references.citation: J Cell Sci. 2012 Sep 1;125(Pt 17):3939-48
references.pmid: 23104738
references.citation: Cancer Res. 2007 Nov 1;67(21):10334-42
references.pmid: 17974976
references.citation: Science. 2001 Dec 21;294(5551):2546-9
references.pmid: 11752575
references.citation: Nat Protoc. 2012 Oct;7(10):1808-17
references.pmid: 22976352
references.citation: Curr Biol. 1998 Feb 12;8(4):243-6
references.pmid: 9501989
references.citation: Science. 2013 Feb 8;339(6120):698-9
references.pmid: 23393264