title: 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.
abstract: Germ-line mutations in breast cancer 1, early onset (BRCA1) result in predisposition to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify p53-binding protein 1 (53BP1) as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell-cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depletion did not alleviate proliferation arrest or checkpoint responses in Brca2-deleted cells. Notably, loss of 53BP1 partially restores the homologous-recombination defect of Brca1-deleted cells and reverts their hypersensitivity to DNA-damaging agents. We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings.
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.forename: Amal
authors.initials: A
authors.lastname: Aly
authors.forename: Jose M
authors.initials: JM
authors.lastname: Escandell
authors.forename: Mark
authors.initials: M
authors.lastname: Pieterse
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Hanneke
authors.initials: H
authors.lastname: van der Gulden
authors.forename: Sanne
authors.initials: S
authors.lastname: Hiddingh
authors.forename: Maria
authors.initials: M
authors.lastname: Thanasoula
authors.forename: Atul
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Haffty
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Madalena
authors.initials: M
authors.lastname: Tarsounas
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics*; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009154:Mutation; D014407:Tumor Cells, Cultured; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1
references.citation: Nat Genet. 2001 Jul;28(3):266-71
references.pmid: 11431698
references.citation: Mol Cell. 2009 Aug 28;35(4):534-41
references.pmid: 19716796
references.citation: Nat Genet. 2000 Nov;26(3):291-9
references.pmid: 11062467
references.citation: J Biol Chem. 2003 Apr 4;278(14):11731-4
references.pmid: 12551891
references.citation: Mol Cell Biol. 2005 Nov;25(22):10079-86
references.pmid: 16260621
references.citation: Physiol Genomics. 2007 Sep 19;31(1):32-41
references.pmid: 17456738
references.citation: Oncogene. 2006 Sep 25;25(43):5885-97
references.pmid: 16998503
references.citation: Nature. 1990 Dec 13;348(6302):649-51
references.pmid: 2250720
references.citation: J Natl Cancer Inst. 2003 Oct 1;95(19):1482-5
references.pmid: 14519755
references.citation: Nucleic Acids Res. 2006 Mar 06;34(5):1416-26
references.pmid: 16522651
references.citation: J Biol Chem. 2000 Aug 4;275(31):23899-903
references.pmid: 10843985
references.citation: Nature. 2009 Dec 17;462(7275):935-9
references.pmid: 20016603
references.citation: Mol Cell Biol. 2006 Dec;26(24):9377-86
references.pmid: 17000754
references.citation: Oncogene. 2006 Sep 25;25(43):5864-74
references.pmid: 16998501
references.citation: Cell. 1997 Aug 8;90(3):425-35
references.pmid: 9267023
references.citation: Cancer Res. 2007 Nov 15;67(22):10669-76
references.pmid: 18006808
references.citation: Biochem Soc Trans. 2006 Nov;34(Pt 5):633-45
references.pmid: 17052168
references.citation: Mol Cell Biol. 2003 Apr;23(7):2556-63
references.pmid: 12640136
references.citation: Nat Genet. 2001 Dec;29(4):418-25
references.pmid: 11694875
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23
references.pmid: 12829800
references.citation: Eur J Cancer. 1997 Mar;33(3):362-71
references.pmid: 9155518
references.citation: Cell. 2002 Jan 25;108(2):171-82
references.pmid: 11832208
references.citation: Nature. 2004 Nov 18;432(7015):316-23
references.pmid: 15549093
references.citation: N Engl J Med. 2009 Jul 9;361(2):123-34
references.pmid: 19553641
references.citation: Science. 2002 Nov 15;298(5597):1435-8
references.pmid: 12364621
references.citation: Mol Cell. 2009 Mar 13;33(5):547-58
references.pmid: 19285939
references.citation: Cancer Res. 2009 Jan 15;69(2):663-71
references.pmid: 19147582
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12111-6
references.pmid: 17626182
references.citation: Nat Genet. 1997 Jul;16(3):298-302
references.pmid: 9207798
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9290-5
references.pmid: 18579772
references.citation: Nat Cell Biol. 2006 Jan;8(1):37-45
references.pmid: 16327781
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12117-22
references.pmid: 17626183
references.citation: Nat Genet. 1992 Oct;2(2):128-31
references.pmid: 1303261
references.citation: Lancet. 2005 Feb 19-25;365(9460):671-9
references.pmid: 15721472
references.citation: Oncogene. 2003 Feb 27;22(8):1115-23
references.pmid: 12606939
references.citation: Oncogene. 2001 Apr 5;20(15):1803-15
references.pmid: 11313928
references.citation: Mol Cell. 2001 Jul;8(1):233-43
references.pmid: 11511376
references.citation: Cell. 2004 Apr 30;117(3):337-47
references.pmid: 15109494
references.citation: Cancer Res. 2008 May 1;68(9):3243-50
references.pmid: 18451150
references.citation: Cancer Cell. 2006 Feb;9(2):121-32
references.pmid: 16473279
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3310-5
references.pmid: 16492765
references.citation: J Clin Oncol. 2010 Mar 1;28(7):1145-53
references.pmid: 20100965
references.citation: Oncogene. 1995 Apr 20;10(8):1673-5
references.pmid: 7731724
references.citation: Cancer Res. 2008 Apr 15;68(8):2581-6
references.pmid: 18413725
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84
references.pmid: 18971340
references.citation: Cell. 1996 Jun 28;85(7):1009-23
references.pmid: 8674108
references.citation: Nat Rev Cancer. 2004 Oct;4(10):814-9
references.pmid: 15510162
references.citation: Genes Dev. 1997 May 15;11(10):1226-41
references.pmid: 9171368
references.citation: Cancer Res. 2009 Apr 15;69(8):3625-33
references.pmid: 19336573
references.citation: Methods Enzymol. 2001;333:247-56
references.pmid: 11400340
references.citation: Nature. 2009 Dec 17;462(7275):886-90
references.pmid: 20016594
references.citation: Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5128-32
references.pmid: 1594621
references.citation: Cancer Cell. 2010 Jan 19;17(1):9-11
references.pmid: 20129245
references.citation: Cell. 2010 Apr 16;141(2):243-54
references.pmid: 20362325