title: ZNF365 promotes stalled replication forks recovery to maintain genome stability.
abstract: The ZNF365 locus is associated with breast cancer risk in carriers of mutated BRCA1 and BRCA2, which are important molecules required for DNA damage response. Previously, we demonstrated that ZNF365 is necessary for timely resolution of replication intermediates of genomic fragile sites and, thus, for suppression of genomic instability; however, the mechanism underlying the function of ZNF365 on damaged DNA and stalled replication forks remains unknown. Here, we demonstrate that ZNF365 is induced by DNA double-strand break (DSB) signals, is involved in the homologous recombination (HR) repair pathway, and maintains genome integrity during DNA replication. On the mechanistic level, ZNF365 interacts with poly(ADP-ribose) polymerase (PARP) 1 to tether MRE11 to the DNA end resection site. Loss of ZNF365 results in delayed mitotic progression and exit due to increased replication stress, ultimately leading to cytokinesis failure, re-duplication of centrosomes, and increased aneuploidy. Collectively, these results suggest an HR repair-dependent function of ZNF365 in preventing genomic instability.
authors: Department of Pathology and Laboratory Medicine; Weill Cornell Medical College; New York, NY USA.
authors: Yuqing
authors: Y
authors: Zhang
authors: Eunmi
authors: E
authors: Park
authors: Christopher S
authors: CS
authors: Kim
authors: Ji-hye
authors: JH
authors: Paik
mesh_terms: D000782:Aneuploidy; D000818:Animals; D048749:Cytokinesis / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D059766:DNA End-Joining Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042822:Genomic Instability; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D051379:Mice; D008938:Mitosis / Q000235:genetics; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C121766:MRE11 protein, human; D014157:Transcription Factors; C475725:ZNF365 protein, human; C587141:ZNF365 protein, mouse; D011065:Poly(ADP-ribose) Polymerases; D000076228:MRE11 Homologue Protein
keywords: PARP1; ZNF365; cell cycle; genomic instability; replication stress
references: Cell Cycle. 2012 Nov 15;11(22):4252-65
references: 23095637
references: Cytogenet Genome Res. 2003;100(1-4):92-100
references: 14526169
references: Nature. 2005 Apr 14;434(7035):917-21
references: 15829967
references: Breast Cancer Res. 2012 Feb 20;14(1):R33
references: 22348646
references: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13057-62
references: 18755892
references: Cell Cycle. 2011 Dec 1;10(23):4039-46
references: 22101264
references: Aging (Albany NY). 2011 Mar;3(3):311-8
references: 21389352
references: Carcinogenesis. 1994 Jan;15(1):33-7
references: 8293545
references: Nature. 2008 Jan 3;451(7174):81-5
references: 18172500
references: Cell. 2010 Apr 16;141(2):243-54
references: 20362325
references: Oncogene. 2004 May 6;23(21):3872-82
references: 15021907
references: Mutat Res. 1999 Mar 8;424(1-2):1-8
references: 10232953
references: Nat Genet. 1999 May;22(1):37-43
references: 10319859
references: DNA Repair (Amst). 2006 Sep 8;5(9-10):1021-9
references: 16807135
references: Genes Dev. 2011 Feb 15;25(4):350-62
references: 21325134
references: Clin Cancer Res. 2010 Apr 15;16(8):2344-51
references: 20371688
references: Cell. 2002 Dec 13;111(6):779-89
references: 12526805
references: EMBO J. 2009 Sep 2;28(17):2601-15
references: 19629035
references: DNA Repair (Amst). 2010 Dec 10;9(12):1273-82
references: 21036673
references: Science. 2002 Jul 26;297(5581):602-6
references: 12142538
references: Cell. 2001 Feb 9;104(3):397-408
references: 11239397
references: Cancer Cell. 2013 May 13;23(5):693-704
references: 23680151
references: Nat Rev Cancer. 2012 Sep;12(9):587-98
references: 22918414
references: Cytogenet Genome Res. 2004;104(1-4):325-32
references: 15162060
references: Genes Dev. 1999 Oct 15;13(20):2633-8
references: 10541549
references: Cancer Res. 2007 Mar 15;67(6):2603-10
references: 17363579
references: J Biol Chem. 2008 Jan 11;283(2):1197-208
references: 18025084
references: Nature. 2005 Apr 14;434(7035):913-7
references: 15829966
references: Genome Integr. 2012 Nov 27;3(1):9
references: 23181949
references: J Cell Biol. 2005 Aug 1;170(3):341-7
references: 16061690
references: Cancer Discov. 2013 Jul;3(7):798-811
references: 23776040
references: J Clin Invest. 2010 Nov;120(11):3834-42
references: 20921626
references: Radiat Res. 1993 May;134(2):209-16
references: 8488254
references: Curr Opin Cell Biol. 2005 Dec;17(6):568-75
references: 16226452
references: Cell Cycle. 2009 Feb 1;8(3):498-504
references: 19177017
references: Cell. 2011 May 13;145(4):529-42
references: 21565612
references: Cancer Res. 2007 Oct 15;67(20):9658-65
references: 17942895
references: Nature. 2004 Oct 21;431(7011):1011-7
references: 15496928
references: Nature. 2006 Oct 5;443(7111):541-7
references: 17024086
references: Cancer Res. 2009 Apr 15;69(8):3625-33
references: 19336573
references: J Cell Biol. 1998 Mar 23;140(6):1285-95
references: 9508763
references: Cancer Res. 2012 Jun 1;72(11):2814-21
references: 22447567
references: PLoS Genet. 2010 Oct 28;6(10):e1001183
references: 21060860
references: J Biol Chem. 2009 Dec 4;284(49):33939-48
references: 19826003
references: Cell Cycle. 2012 Nov 1;11(21):3983-96
references: 22987153
references: Cell Cycle. 2005 Sep;4(9):1176-8
references: 16123586