靶向同源重组蛋白Rad51在乳腺癌作用机制中的研究现状
|
摘要
重组蛋白Rad51是通过同源重组来修复DNA双链断裂(double-strand breaks,DSBs)的核心因子,Rad51在正常组织中低表达或不表达,在乳腺癌组织中高表达,其主要机制是通过参与同源重组信号通路中Rad51核蛋白丝形成并影响多种细胞因子来发挥DNA修复作用。近年来,随着对Rad51蛋白的研究,发现高表达Rad51会调控乳腺癌细胞增殖、侵袭、预后及对放化疗药物敏感性。有效下调肿瘤组织中的Rad51的水平,可降低肿瘤细胞的DNA损伤修复能力,从而提高肿瘤治疗的疗效。因此了解Rad51的作用机制及开发Rad51蛋白抑制剂成为乳腺癌治疗的新靶点。目前,具有Rad51抑制活性的小分子化合物来源广泛,多数是针对Rad51核蛋白丝形成过程中的结构而设计并合成的化合物。本文回顾Rad51蛋白在同源重组过程中的作用机制和乳腺癌进展关系,并对近年来研究较热的Rad51抑制剂及新型相关抑制剂最新研究现状进行总结。
The recombinant protein Rad51 is a core factor for repairing double-strand breaks(DSBs) by homologous recombination. RAD51 is low or not expressed in normal tissues,but highly in breast cancer tissues,the mechanism of action is mainly involved in Rad51 nuclear protein filament formation in the homologous recombination signaling pathway and affecting a variety of cytokines to repair DNA. In recent years,with the study of high expression of Rad51 protein,it is found that it can participate in the regulation of breast cancer cell proliferation,invasion,prognosis and sensitivity to chemoradiotherapy drugs. How to effectively reduce the level of Rad51 in tumor tissues can reduce the DNA damage repair ability of tumor cells,and thus improve the therapeutic effect of tumor treatment. Therefore,understanding the mechanism of RAD51 and developing RAD51 protein inhibitors have become novel targets for breast cancer treatment. At present,small molecule compounds having Rad51 inhibitory activity are widely available,and most of the compounds are designed and synthesized for the structure of the Rad51 nuclear protein filament formation process. This article reviews the relationship between the mechanism of Rad51 protein in the process of homologous recombination and the progression of breast cancer,and summarizes the recentresearch status of Rad51 inhibitors and novel related inhibitors in recent years.
The recombinant protein Rad51 is a core factor for repairing double-strand breaks(DSBs) by homologous recombination. RAD51 is low or not expressed in normal tissues,but highly in breast cancer tissues,the mechanism of action is mainly involved in Rad51 nuclear protein filament formation in the homologous recombination signaling pathway and affecting a variety of cytokines to repair DNA. In recent years,with the study of high expression of Rad51 protein,it is found that it can participate in the regulation of breast cancer cell proliferation,invasion,prognosis and sensitivity to chemoradiotherapy drugs. How to effectively reduce the level of Rad51 in tumor tissues can reduce the DNA damage repair ability of tumor cells,and thus improve the therapeutic effect of tumor treatment. Therefore,understanding the mechanism of RAD51 and developing RAD51 protein inhibitors have become novel targets for breast cancer treatment. At present,small molecule compounds having Rad51 inhibitory activity are widely available,and most of the compounds are designed and synthesized for the structure of the Rad51 nuclear protein filament formation process. This article reviews the relationship between the mechanism of Rad51 protein in the process of homologous recombination and the progression of breast cancer,and summarizes the recentresearch status of Rad51 inhibitors and novel related inhibitors in recent years.
引文
[1]FITZMAURICE C,ALLEN C,BARBER RM,et al.Global,regional,and national cancer incidence,mortality,years of life lost,years lived with disability,and disability-adjusted life-years for 32 cancer groups,1990 to 2015:a systematic analysis for the global burden of disease study[J].Jama Oncology,2017,3(4):524-548.
[2]CARVALHO JF,KANAAR R.Targeting homologous recombination-mediated DNA repair in cancer[J].Expert Opin Ther Targets,2014,18(4):427-458.
[3]MATEO J,BOYSEN G,BARBIERI CE,et al.DNA repair in prostate cancer:biology and clinical implications[J].Eur Urol,2017,71(3):417-425.
[4]MCLORNAN DP,LIST A,MUFTI GJ.Applying synthetic lethality for the selective targeting of cancer[J].N Engl J Med,2014,371(18):1725-1735.
[5]LI BX,CHEN J,CHAO B.A lamin-binding ligand inhibits homologous recombination repair of DNA double-strand breaks[J].ACS Cent Sci,2018,4(9):1201-1210.
[6]CHEN Q,CAI D,LI M,et al.The homologous recombination protein RAD51 is a promisingtherapeutic target for cervical carcinoma[J].Oncol Rep,2017,38(2):767-774.
[7]LIU Y,BURNESS ML,MARTIN-TREVINO R,et al.RAD51mediates resistance of cancer stem cells to PARP inhibition in triple-negative breast cancer[J].Clin Cancer Res,2017,23(2):514-522.
[8]ALSHAREEDA AT,NEGM OH,ALESKANDARANY MA,et al.Clinical and biological significance of RAD51 expression in breast cancer:a key DNA damage response protein[J].Breast Cancer Res Treat,2016,159(1):41-53.
[9]DENT R,TRUDEAU M,PRITCHARD KI,et al.Triple-negative breast cancer:clinical features and patterns of recurrence[J].Clin Cancer Res,2018,13(15):4429-4434.
[10]HYMAN DM,SOLIT DB,ARRCILA ME,et al.Precision medicine at memorial sloan kettering cancer center:clinical next-generation sequencing enabling next-generation targeted therapy trials[J].Drug Discov Today,2015,20(12):1422-1428.
[11]HINE CM,SELUANOV A,GORBUNOVA V.Use of the Rad51promoter for targeted anti-cancer therapy[J].Proc Natl Acad Sci USA,2008,105(52):20810-20815.
[12]XU J,ZHAO L,XU Y,et al.Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange[J].Nat Struct Mol Biol,2017,24(1):40-46.
[13]SHORT JM,LIU Y,CHEN S,et al.High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy[J].Nucleic Acids Res,2016,44(19):9017-9030.
[14]WANG AT,KIM T,WAGNER JE,et al.A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination[J].Mol Cell,2015,59(3):478-490.
[15]RANJHA L,HOWARD SM,CEJKA P.Main steps in DNAdouble-strand break repair:an introduction to homologous recombination and related processes[J].Chromosoma,2018,127(2):187-214.
[16]XU J,ZHAO L,XU Y,et al.Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange[J].Nat Struct Mol Biol,2017,24(1):40-46.
[17]HUANG TH,FOLWLER FC,CHEN CC,et al.The histone chaperones ASF1 and CAF-1 promote MMS22L-TONSL-mediated Rad51 loading onto ss DNA during homologous recombination in human cells[J].Mol Cell,2018,69(5):879-892.
[18]DUNGRAWALA H,BHAT KP,LE MERU R,et al.RADXpromotes genome stability and modulates chemosensitivity by regulating RAD51 at replication forks[J].Mol Cell,2017,67(3):374-386.
[19]GLENDINING KA,MARKIE D,GARDNER RJM,et al.A novel role for the DNA repair gene Rad51 in Netrin-1 signalling[J].Sci Rep,2017,7:39823.
[20]BHATTACHARYA S,SRINIVASAN K,ABDISALAAM S,et al.RAD51 interconnects between DNA replication,DNA repair and immunity[J].Nucleic Acids Res,2017,45(8):4590-4605.
[21]MOIANI D,RONATO DA,BROSEY CA,et al.Targeting allostery with avatars to design inhibitors assessed by cell activity:dissecting MRE11 endo-and exonuclease activities[J].Methods Enzymol,2018,601:205-241.
[22]LU CH,CHANG TT,CHO CC,et al.Stable nuclei of nucleoprotein filament and high ss DNA binding affinity contribute to enhanced Rec A E38K recombinase activity[J].Sci Rep,2017,7(1):14964
[23]PRAKASH R,ZHANG Y,FENG W,et al.Homologous recombination and human health:the roles of BRCA1,BRCA2,and associated proteins[J].Cold Spring Harb Perspect Biol,2015,7(4):a016600-29.
[24]REUTER M,ZELENSKY A,SMAL I,et al.BRCA2 diffuses as oligomeric clusters with RAD51 and changes mobility after DNAdamage in live cells[J].J Cell Biol,2015,207(5):599-613.
[25]SHAHID T,SOROKA J,KONG E,et al.Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor[J].Nat Struct Mol Biol,2014,21(11):962-968.
[26]MA CJ,KWON Y,SUNG P,et al.Human RAD52 interactions with replication protein A and the RAD51 presynaptic complex[J].J Biol Chem,2017,292(28):11702-11713.
[27]CHU JM,GIBB B,KWON YH,et al.Protein dynamics of human RPA and RAD51 on ss DNA during assembly and disassembly of the RAD51 filament[J].Nucleic Acids Res,2016,45(2):749-761.
[28]QI Z,REDDING S,LEE JY,et al.DNA sequence alignment by microhomology sampling during homologous recombination[J].Cell,2015,160(5):856-869.
[29]VASIANOVICH Y,ALTMANNOVA V,KOTENKO O,et al.Unloading of homologous recombination factors is required for restoring double-stranded DNA at damage repair loci[J].EMBOJ,2017,36(2):213-231.
[30]LEE JY,QI Z,GREENE EC.ATP hydrolysis promotes duplex DNA release by the Rec A presynaptic complex[J].J Bio Chem,2016,291(42):22218-22230.
[31]MANJUNATH GP,SONI N,VADDAVALLI PL,et al.Molecular mechanism underlying ATP-induced conformational changes in nucleoprotein filament of Mycobacterium smegmatis Rec A[J].Biochem,2016,55(12):1850-1862.
[32]RANJHA L,HOWARD SM,CEJKA P.Main steps in DNAdouble-strand break repair:an introduction to homologous recombination and related processes[J].Chromosoma,2018,127(2):187-214.
[33]BROUWER I,MOSCHETTI T,CANDELLI A,et al.Two distinct conformational states define the interaction of human RAD51-ATP with single-stranded DNA[J].Embo J,2018,37(7):e98162.
[34]WRIGHT WD,HEYER WD.Rad54 functions as a heteroduplex DNA pump modulated by its DNA substrates and Rad51 during Dloop formation[J].Mol Cell,2014,53(3):420-432.
[35]MASON JM,DUSAD K,WRIGHT WD,et al.RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells[J].Nucleic Acids Res,2015,43(6):3180-3196.
[36]VAN MJ,MODESTI M,KANAAR R,et al.Counting RAD51proteins disassembling from nucleoprotein filaments under tension[J].Nature,2009,457(7230):745-748.
[37]SHORT JM,LIU Y,CHEN S,et al.High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy[J].Nucleic Acids Res,2016,44(19):9017-9030.
[38]CHANG HY,LIAO CY,SU GC,et al.Functional relationship of ATP hydrolysis,presynaptic filament stability,and homologous DNA pairing activity of the human meiotic recombinase DMC1[J].J Bio Chem,2015,290(32):19863-19873.
[39]KOWALCZYKOWSKI SC.An overview of the molecular mechanisms of recombinational DNA repair[J].Cold Spring Harb Perspect Biol,2015,7(11):a016410.
[40]CHU JM,GIBB B,KWON YH,et al.Protein dynamics of human RPA and RAD51 on ss DNA during assembly and disassembly of the RAD51 filament[J].Nucleic Acids Res,2017,45(2):749-761.
[41]DAVENPORT EP,HARRIS DF,ORIGANTI S,et al.Rad51nucleoprotein filament disassembly captured using fluorescent plasmodium falciparum SSB as a reporter for single-stranded DNA[J].Plos One,2016,11(7):e0159242.
[42]KANIECKI K,TULLIO LD,GIBB B,et al.Dissociation of Rad51 presynaptic complexes and heteroduplex DNA joints by tandem assemblies of Srs2[J].Cell Rep,2017,21(11):3166-3177.
[43]HALLAJIAN Z,MAHJOUBI F,NAFISSI N.Simultaneous ATM/BRCA1/RAD51,expression variations associated with prognostic factors in Iranian sporadic breast cancer patients[J].Breast Cancer,2017,24(4):624-634.
[44]GACHECHILADZE M,SKARDA J,SOLTERMANN A,et al.RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies[J].Int J Cancer,2017,141(7):1286-1294.
[45]WIEGMANS AP,AL-EJEH F,CHEE N,et al.Rad51 supports triple negative breast cancer metastasis[J].Oncotarget,2014,5(10):3261-3272.
[46]HUANG F,MAZIN AV.A small molecule inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts[J].PloS One,2014,9(6):e100993.
[47]SODERLUND LK,ASKLID A,FORNANDER T,et al.The RAD51 135G>C polymorphism is related to the effect of adjuvant therapy in early breast cancer[J].J Cancer Res Clin Oncol,2015,141(5):797-804.
[48]CHEN J,MORRICAL MD,DONIGAN KA,et al.Tumor-associated mutations in a conserved structural motif alter physical and biochemical properties of human RAD51 recombinase[J].Nucleic Acids Res,2015,43(2):1098-1111.
[49]HINE CM,SELUANOV A,GORBUNOVA V.Rad51 promotertargeted gene therapy is effective for in vivo visualization and treatment of cancer[J].Mol Ther,2012,20(2):347-355.
[50]HUANG F,MOTLEKAR NA,BURGWIN CM,et al.Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening[J].Acs Che Biol,2011,6(6):628-635.
[51]BUDKE B,LV W,KOZIKOWSKI AP,et al.Recent developments using small molecules to target RAD51:how to best modulate RAD51 for anticancer therapy?[J].Chem Med Chem,2016,11(22):2468-2473.
[52]ALAGPULINSA DA,AYYADEVARA S,SHMOOKLER RJ.Asmall-molecule inhibitor of RAD51 reduces homologous recombination and sensitizes multiple myeloma cells to doxorubicin[J].Fron Oncol,2014,4:289.
[53]NORMAND A,RIVIERE E,RENODON A.Identification and characterization of human Rad51 inhibitors by screening of an existing drug library[J].Biochem Pharm,2014,91(3):293-300.
[54]ZHU J,CHEN H,GUO XE,et al.Synthesis,molecular modeling,and biological evaluation of novel RAD51 inhibitors[J].Eur J Med Chem,2015,96:196-208.
[55]FERGUSON PJ,VINCENT MD,KOROPATNICK J.Synergistic antiproliferative activity of the RAD51 inhibitor IBR2 with inhibitors of receptor tyrosine kinases and microtubule protein[J].JPharm Exp Ther,2018,364(1):46-54.
[56]TAKAKU M,KAINUMA T,ISHIDA-TAKAKU T,et al.Halenaquinone,a chemical compound that specifically inhibits the secondary DNA binding of RAD51[J].Genes Cells,2011,16(4):427-436.
[57]LV W,BUDKE B,PAWLOWSKI M,et al.Development of small molecules that specifically inhibit the D-loop activity of RAD51[J].J Med Chem,2016,50(10):4511-4525.
[58]TURCHICK A,HEGAN DC,JENSEN RB,et al.A cell-penetrating antibody inhibits human RAD51 via direct binding[J].Nucleic Acids Res,2017,45(20):11782-11799.
[59]SCOTT DE,COYNE AG,VENKITARAMAN A,et al.Smallmolecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases[J].Chem Med Chem,2015,10(2):296-303.
[2]CARVALHO JF,KANAAR R.Targeting homologous recombination-mediated DNA repair in cancer[J].Expert Opin Ther Targets,2014,18(4):427-458.
[3]MATEO J,BOYSEN G,BARBIERI CE,et al.DNA repair in prostate cancer:biology and clinical implications[J].Eur Urol,2017,71(3):417-425.
[4]MCLORNAN DP,LIST A,MUFTI GJ.Applying synthetic lethality for the selective targeting of cancer[J].N Engl J Med,2014,371(18):1725-1735.
[5]LI BX,CHEN J,CHAO B.A lamin-binding ligand inhibits homologous recombination repair of DNA double-strand breaks[J].ACS Cent Sci,2018,4(9):1201-1210.
[6]CHEN Q,CAI D,LI M,et al.The homologous recombination protein RAD51 is a promisingtherapeutic target for cervical carcinoma[J].Oncol Rep,2017,38(2):767-774.
[7]LIU Y,BURNESS ML,MARTIN-TREVINO R,et al.RAD51mediates resistance of cancer stem cells to PARP inhibition in triple-negative breast cancer[J].Clin Cancer Res,2017,23(2):514-522.
[8]ALSHAREEDA AT,NEGM OH,ALESKANDARANY MA,et al.Clinical and biological significance of RAD51 expression in breast cancer:a key DNA damage response protein[J].Breast Cancer Res Treat,2016,159(1):41-53.
[9]DENT R,TRUDEAU M,PRITCHARD KI,et al.Triple-negative breast cancer:clinical features and patterns of recurrence[J].Clin Cancer Res,2018,13(15):4429-4434.
[10]HYMAN DM,SOLIT DB,ARRCILA ME,et al.Precision medicine at memorial sloan kettering cancer center:clinical next-generation sequencing enabling next-generation targeted therapy trials[J].Drug Discov Today,2015,20(12):1422-1428.
[11]HINE CM,SELUANOV A,GORBUNOVA V.Use of the Rad51promoter for targeted anti-cancer therapy[J].Proc Natl Acad Sci USA,2008,105(52):20810-20815.
[12]XU J,ZHAO L,XU Y,et al.Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange[J].Nat Struct Mol Biol,2017,24(1):40-46.
[13]SHORT JM,LIU Y,CHEN S,et al.High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy[J].Nucleic Acids Res,2016,44(19):9017-9030.
[14]WANG AT,KIM T,WAGNER JE,et al.A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination[J].Mol Cell,2015,59(3):478-490.
[15]RANJHA L,HOWARD SM,CEJKA P.Main steps in DNAdouble-strand break repair:an introduction to homologous recombination and related processes[J].Chromosoma,2018,127(2):187-214.
[16]XU J,ZHAO L,XU Y,et al.Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange[J].Nat Struct Mol Biol,2017,24(1):40-46.
[17]HUANG TH,FOLWLER FC,CHEN CC,et al.The histone chaperones ASF1 and CAF-1 promote MMS22L-TONSL-mediated Rad51 loading onto ss DNA during homologous recombination in human cells[J].Mol Cell,2018,69(5):879-892.
[18]DUNGRAWALA H,BHAT KP,LE MERU R,et al.RADXpromotes genome stability and modulates chemosensitivity by regulating RAD51 at replication forks[J].Mol Cell,2017,67(3):374-386.
[19]GLENDINING KA,MARKIE D,GARDNER RJM,et al.A novel role for the DNA repair gene Rad51 in Netrin-1 signalling[J].Sci Rep,2017,7:39823.
[20]BHATTACHARYA S,SRINIVASAN K,ABDISALAAM S,et al.RAD51 interconnects between DNA replication,DNA repair and immunity[J].Nucleic Acids Res,2017,45(8):4590-4605.
[21]MOIANI D,RONATO DA,BROSEY CA,et al.Targeting allostery with avatars to design inhibitors assessed by cell activity:dissecting MRE11 endo-and exonuclease activities[J].Methods Enzymol,2018,601:205-241.
[22]LU CH,CHANG TT,CHO CC,et al.Stable nuclei of nucleoprotein filament and high ss DNA binding affinity contribute to enhanced Rec A E38K recombinase activity[J].Sci Rep,2017,7(1):14964
[23]PRAKASH R,ZHANG Y,FENG W,et al.Homologous recombination and human health:the roles of BRCA1,BRCA2,and associated proteins[J].Cold Spring Harb Perspect Biol,2015,7(4):a016600-29.
[24]REUTER M,ZELENSKY A,SMAL I,et al.BRCA2 diffuses as oligomeric clusters with RAD51 and changes mobility after DNAdamage in live cells[J].J Cell Biol,2015,207(5):599-613.
[25]SHAHID T,SOROKA J,KONG E,et al.Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor[J].Nat Struct Mol Biol,2014,21(11):962-968.
[26]MA CJ,KWON Y,SUNG P,et al.Human RAD52 interactions with replication protein A and the RAD51 presynaptic complex[J].J Biol Chem,2017,292(28):11702-11713.
[27]CHU JM,GIBB B,KWON YH,et al.Protein dynamics of human RPA and RAD51 on ss DNA during assembly and disassembly of the RAD51 filament[J].Nucleic Acids Res,2016,45(2):749-761.
[28]QI Z,REDDING S,LEE JY,et al.DNA sequence alignment by microhomology sampling during homologous recombination[J].Cell,2015,160(5):856-869.
[29]VASIANOVICH Y,ALTMANNOVA V,KOTENKO O,et al.Unloading of homologous recombination factors is required for restoring double-stranded DNA at damage repair loci[J].EMBOJ,2017,36(2):213-231.
[30]LEE JY,QI Z,GREENE EC.ATP hydrolysis promotes duplex DNA release by the Rec A presynaptic complex[J].J Bio Chem,2016,291(42):22218-22230.
[31]MANJUNATH GP,SONI N,VADDAVALLI PL,et al.Molecular mechanism underlying ATP-induced conformational changes in nucleoprotein filament of Mycobacterium smegmatis Rec A[J].Biochem,2016,55(12):1850-1862.
[32]RANJHA L,HOWARD SM,CEJKA P.Main steps in DNAdouble-strand break repair:an introduction to homologous recombination and related processes[J].Chromosoma,2018,127(2):187-214.
[33]BROUWER I,MOSCHETTI T,CANDELLI A,et al.Two distinct conformational states define the interaction of human RAD51-ATP with single-stranded DNA[J].Embo J,2018,37(7):e98162.
[34]WRIGHT WD,HEYER WD.Rad54 functions as a heteroduplex DNA pump modulated by its DNA substrates and Rad51 during Dloop formation[J].Mol Cell,2014,53(3):420-432.
[35]MASON JM,DUSAD K,WRIGHT WD,et al.RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells[J].Nucleic Acids Res,2015,43(6):3180-3196.
[36]VAN MJ,MODESTI M,KANAAR R,et al.Counting RAD51proteins disassembling from nucleoprotein filaments under tension[J].Nature,2009,457(7230):745-748.
[37]SHORT JM,LIU Y,CHEN S,et al.High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy[J].Nucleic Acids Res,2016,44(19):9017-9030.
[38]CHANG HY,LIAO CY,SU GC,et al.Functional relationship of ATP hydrolysis,presynaptic filament stability,and homologous DNA pairing activity of the human meiotic recombinase DMC1[J].J Bio Chem,2015,290(32):19863-19873.
[39]KOWALCZYKOWSKI SC.An overview of the molecular mechanisms of recombinational DNA repair[J].Cold Spring Harb Perspect Biol,2015,7(11):a016410.
[40]CHU JM,GIBB B,KWON YH,et al.Protein dynamics of human RPA and RAD51 on ss DNA during assembly and disassembly of the RAD51 filament[J].Nucleic Acids Res,2017,45(2):749-761.
[41]DAVENPORT EP,HARRIS DF,ORIGANTI S,et al.Rad51nucleoprotein filament disassembly captured using fluorescent plasmodium falciparum SSB as a reporter for single-stranded DNA[J].Plos One,2016,11(7):e0159242.
[42]KANIECKI K,TULLIO LD,GIBB B,et al.Dissociation of Rad51 presynaptic complexes and heteroduplex DNA joints by tandem assemblies of Srs2[J].Cell Rep,2017,21(11):3166-3177.
[43]HALLAJIAN Z,MAHJOUBI F,NAFISSI N.Simultaneous ATM/BRCA1/RAD51,expression variations associated with prognostic factors in Iranian sporadic breast cancer patients[J].Breast Cancer,2017,24(4):624-634.
[44]GACHECHILADZE M,SKARDA J,SOLTERMANN A,et al.RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies[J].Int J Cancer,2017,141(7):1286-1294.
[45]WIEGMANS AP,AL-EJEH F,CHEE N,et al.Rad51 supports triple negative breast cancer metastasis[J].Oncotarget,2014,5(10):3261-3272.
[46]HUANG F,MAZIN AV.A small molecule inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts[J].PloS One,2014,9(6):e100993.
[47]SODERLUND LK,ASKLID A,FORNANDER T,et al.The RAD51 135G>C polymorphism is related to the effect of adjuvant therapy in early breast cancer[J].J Cancer Res Clin Oncol,2015,141(5):797-804.
[48]CHEN J,MORRICAL MD,DONIGAN KA,et al.Tumor-associated mutations in a conserved structural motif alter physical and biochemical properties of human RAD51 recombinase[J].Nucleic Acids Res,2015,43(2):1098-1111.
[49]HINE CM,SELUANOV A,GORBUNOVA V.Rad51 promotertargeted gene therapy is effective for in vivo visualization and treatment of cancer[J].Mol Ther,2012,20(2):347-355.
[50]HUANG F,MOTLEKAR NA,BURGWIN CM,et al.Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening[J].Acs Che Biol,2011,6(6):628-635.
[51]BUDKE B,LV W,KOZIKOWSKI AP,et al.Recent developments using small molecules to target RAD51:how to best modulate RAD51 for anticancer therapy?[J].Chem Med Chem,2016,11(22):2468-2473.
[52]ALAGPULINSA DA,AYYADEVARA S,SHMOOKLER RJ.Asmall-molecule inhibitor of RAD51 reduces homologous recombination and sensitizes multiple myeloma cells to doxorubicin[J].Fron Oncol,2014,4:289.
[53]NORMAND A,RIVIERE E,RENODON A.Identification and characterization of human Rad51 inhibitors by screening of an existing drug library[J].Biochem Pharm,2014,91(3):293-300.
[54]ZHU J,CHEN H,GUO XE,et al.Synthesis,molecular modeling,and biological evaluation of novel RAD51 inhibitors[J].Eur J Med Chem,2015,96:196-208.
[55]FERGUSON PJ,VINCENT MD,KOROPATNICK J.Synergistic antiproliferative activity of the RAD51 inhibitor IBR2 with inhibitors of receptor tyrosine kinases and microtubule protein[J].JPharm Exp Ther,2018,364(1):46-54.
[56]TAKAKU M,KAINUMA T,ISHIDA-TAKAKU T,et al.Halenaquinone,a chemical compound that specifically inhibits the secondary DNA binding of RAD51[J].Genes Cells,2011,16(4):427-436.
[57]LV W,BUDKE B,PAWLOWSKI M,et al.Development of small molecules that specifically inhibit the D-loop activity of RAD51[J].J Med Chem,2016,50(10):4511-4525.
[58]TURCHICK A,HEGAN DC,JENSEN RB,et al.A cell-penetrating antibody inhibits human RAD51 via direct binding[J].Nucleic Acids Res,2017,45(20):11782-11799.
[59]SCOTT DE,COYNE AG,VENKITARAMAN A,et al.Smallmolecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases[J].Chem Med Chem,2015,10(2):296-303.