title: Enhanced levels of double-strand DNA break repair proteins protect ovarian cancer cells against genotoxic stress-induced apoptosis.
abstract: BACKGROUND
  Earlier, proteomic profiling of a Serous Ovarian Carcinoma (SeOvCa) progression model in our lab had identified significantly enriched expression of three double-strand break (DSB) -repair proteins viz. RAD50, NPM1, and XRCC5 in transformed cells over pre-transformed, non-tumorigenic cells. Analysis of the functional relevance of enhanced levels of these proteins was explored in transformed ovarian cancer cells.
  
  
  METHODS
  Expression profiling, validation and quantitation of the DSB-repair proteins at the transcriptional and protein levels were carried out. Further analyses included identification of their localization, distribution and modulation on exposure to Estradiol (E2) and cisplatin. Effects on silencing of each of these under conditions of genomic-stress were studied with respect to apoptosis, alterations in nuclear morphology and DNA fragmentation; besides profiling known mitotic and spindle check-point markers in DSB-repair.
  
  
  RESULTS
  We identified that levels of these DSB-repair proteins were elevated not only in our model, but generally in cancer and are specifically triggered in response to genotoxic stress. Silencing of their expression led to aberrant DSB repair and consequently, p53/p21 mediated apoptosis. Further compromised functionality generated genomic instability.
  
  
  CONCLUSIONS
  Present study elucidates a functional relevance of NPM1, RAD50 and XRCC5 DSB-repair proteins towards ensuring survival and evasion of apoptosis during ovarian transformation, emphasizing their contribution and association with disease progression in high-grade SeOvCa.
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune University Campus, Ganeshkhind, Pune 411 007, India. sabapat@nccs.res.in.
authors.forename: Rajkumar Singh
authors.initials: RS
authors.lastname: Kalra
authors.forename: Sharmila A
authors.initials: SA
authors.lastname: Bapat
references.citation: J Biol Chem. 2002 Dec 13;277(50):48234-40
references.pmid: 12374805
references.citation: Curr Protoc Immunol. 2001 May;Chapter 10:Unit 10.11
references.pmid: 18432674
references.citation: Cancer Res. 2010 Jun 15;70(12):4809-19
references.pmid: 20530682
references.citation: PLoS One. 2012;7(9):e45484
references.pmid: 23029043
references.citation: Science. 2008 Mar 7;319(5868):1352-5
references.pmid: 18323444
references.citation: Stem Cells. 2009 Sep;27(9):2059-68
references.pmid: 19544473
references.citation: PLoS One. 2013 Aug 06;8(8):e70398
references.pmid: 23936423
references.citation: Nature. 2005 Apr 14;434(7035):907-13
references.pmid: 15829965
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1021-9
references.pmid: 16807135
references.citation: Nature. 2011 Jun 29;474(7353):609-15
references.pmid: 21720365
references.citation: Nature. 2004 Nov 18;432(7015):316-23
references.pmid: 15549093
references.citation: J Biol Chem. 2001 Jun 15;276(24):21529-37
references.pmid: 11278991
references.citation: J Pathol. 2010 May;221(1):49-56
references.pmid: 20229506
references.citation: Biochemistry. 1987 Jun 16;26(12):3303-7
references.pmid: 3651385
references.citation: J Biol Chem. 1988 Sep 5;263(25):12705-8
references.pmid: 3045126
references.citation: Cancer Res. 2010 Sep 1;70(17):6746-56
references.pmid: 20713529
references.citation: Oncogene. 2006 Oct 12;25(47):6336-44
references.pmid: 16732329
references.citation: Mol Cell. 2006 Jan 20;21(2):201-14
references.pmid: 16427010
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8164-9
references.pmid: 12808131
references.citation: Cancer Res. 2005 Apr 15;65(8):3025-9
references.pmid: 15833827
references.citation: Nat Rev Cancer. 2004 Mar;4(3):216-25
references.pmid: 14993903
references.citation: J Pathol. 2012 Feb;226(3):421-6
references.pmid: 21990067
references.citation: Nature. 2002 Aug 1;418(6897):562-6
references.pmid: 12152085
references.citation: Mol Cell Biol. 2005 Oct;25(20):8874-86
references.pmid: 16199867
references.citation: Cancer Res. 1987 Dec 15;47(24 Pt 1):6517-21
references.pmid: 3677090
references.citation: Nat Cell Biol. 2002 Jul;4(7):529-33
references.pmid: 12080348
references.citation: Differentiation. 2010 Apr-Jun;79(4-5):218-31
references.pmid: 20207472
references.citation: EMBO J. 1998 Mar 16;17(6):1819-28
references.pmid: 9501103