RNF8/RNF168信号通路在DNA损伤修复中的作用
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摘要
细胞内DNA会受部分外界因素(如紫外辐射,电离辐射和化学毒素)和内部因素(如复制错误)的影响而发生损伤,包括DNA双链断裂、DNA错配和DNA交链等。DNA损伤发生后,损伤部位会被一些蛋白识别,进而招募一系列蛋白至损伤部位,形成一个修复系统。DNA双链断裂是最严重的一种DNA损伤,错误修复往往导致疾病的发生。DNA双链断裂(double strand break, DSB)后,细胞启动RNF8/RNF168信号通路进行修复。RNF8和RNF168是这条通路的枢纽蛋白;53BP和BRCA1是关键的效应蛋白,决定着DSB修复的方式;组蛋白泛素化、磷酸化和甲基化等翻译后修饰是这条通路顺利进行的基本条件;染色质重塑、泛素化酶/去泛素化酶平衡和蛋白稳定性是这条通路的主要调节方式。本综述对RNF8/RNF168信号通路进行了梳理总结,希望其能对相关研究者起到参考作用。
DNA damage happens once it is affected by some external factors(such as ultraviolet radiation, ionizing radiation and chemical toxins) and internal factors(such as replication error). DNA damage includes DNA double strand breaks, DNA mismatch and DNA cross-linking etc. After DNA damage occurs, the site of injury is identified by a number of proteins, and then a series of proteins are recruited to the site of injury to form a repair system. DNA double strand break is the most serious type of DNA damage, and error repair often leads to the occurrence of disease.RNF8/RNF168 signaling pathway is activated for repair when cells meet with DNA double strand break(DSB). RNF8 and RNF168 are hinge proteins in this pathway, and 53 BP and BRCA1 are key effector proteins which determine the way of DSB repair. Post-translational modifications of histone such as ubiquitination, phosphorylation and methylation are the basic conditions for the smooth progress of this pathway. Chromatin remodeling, ubiquitin enzyme/deubiquitinase balance and protein stability are the main regulation types of this pathway. This review summarized the RNF8/RNF168 signaling pathway and hoped it could serve as a reference to the relevant researchers.
DNA damage happens once it is affected by some external factors(such as ultraviolet radiation, ionizing radiation and chemical toxins) and internal factors(such as replication error). DNA damage includes DNA double strand breaks, DNA mismatch and DNA cross-linking etc. After DNA damage occurs, the site of injury is identified by a number of proteins, and then a series of proteins are recruited to the site of injury to form a repair system. DNA double strand break is the most serious type of DNA damage, and error repair often leads to the occurrence of disease.RNF8/RNF168 signaling pathway is activated for repair when cells meet with DNA double strand break(DSB). RNF8 and RNF168 are hinge proteins in this pathway, and 53 BP and BRCA1 are key effector proteins which determine the way of DSB repair. Post-translational modifications of histone such as ubiquitination, phosphorylation and methylation are the basic conditions for the smooth progress of this pathway. Chromatin remodeling, ubiquitin enzyme/deubiquitinase balance and protein stability are the main regulation types of this pathway. This review summarized the RNF8/RNF168 signaling pathway and hoped it could serve as a reference to the relevant researchers.
引文
Al-Hakim A.,Escribano-Diaz C.,Landry M.C.,O'Donnell L.,Panier S.,Szilard R.K.,and Durocher D.,2010,The ubiquitous role of ubiquitin in the DNA damage response,DNA Repair,9(12):1229-1240
Bartocci C.,and Denchi E.L.,2013,Put a RING on it:regulation and inhibition of RNF8 and RNF168 RING finger E3 ligases at DNA damage sites,Frontiers in Genetics,4(128):1-12
Bekker-Jensen S.,Danielsen J.R.,Fugger K.,Gromova I.,Nerstedt A.,Lukas C.,and Mail N.,2010,HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes,Nature Cell Biology,(12):80-86
Botuyan M.V.,Lee J.,Ward I.M.,Kim J.E.,Thompson J.R.,Chen J.,and Mer G.,2006,Structural basis for the methylation statespecific recognition of histone H4-K20 by 53BP1 and Crb2in DNA repair,Cell,127(7):1361-1373
Doil C.,Mailand N.,Bekker-Jensen S.,Menard P.,Larsen D.H.,Pepperkok R.,Ellenberg J.,Panier S.,Durocher D.,Bartek J.,Lukas J.,and Lukas C.,2009,RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins,Cell,136(3):435-446
Fradet-Turcotte A.,Canny M.D.,and Escribano-Diaz C.,2013,53BP1 is a reader of the DNA-damage-induced H2A Lys 15ubiquitin mark,Nature,499(7456):50-54
Gudjonsson T.,Altmeyer M.,Savic V.,Toledo L.,Dinant C.,and Gr尴fte M.,2012,TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes,Cell,150(4):697-709
Guturi K.K.N.,Bohgaki M.,Bohgaki T.,Srikumar T.,Ng D.,Kumareswaran R.,Ghamrashi S.E.,Jeon J.,Patel P.,Eldin M.S.,Bristow R.,Cheung P.,Stewart G.S.,Raught B.,Hakem A.,and Hakem R.,2016,RNF168 and USP10 regulate topoisomerase IIαfunction via opposing effects on its ubiquitylation,Nature Communications,7(12638):1-13
Huen M.S.,Grant R.,Manke I.,Minn K.,Yu X.,Yaffe M.B.,and Chen J.,2007,RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly,Cell,131(5):901-914
Jackson S.P.,and Bartek J.,2009,The DNA-damage response in human biology and disease,Nature,461(7267):1071-1078
Jackson S.P.,and Durocher D.,2013,Regulation of DNA damage responses by ubiquitin and SUMO,Molecular Cell,49(5):795-807
Jeggo P.A.,and Lobrich M.,2007,DNA double-strand breaks:their cellular and clinical impact,Oncogene,26(56):7717-7719
Joo H.Y.,Zhai L.,Yang C.Y.,Nie S.Y.,Erdjument-Bromage H.,and Tempst P.,2007,Regulation of cell cycle progression and gene expression by H2A deubiquitination,Nature,449:1068-1072
Kakarougkas A.,and Jeggo P.A.,2014,DNA DSB repair pathway choice:an orchestrated handover mechanism,The British Journal of Radiology,87(1035):20130685
Kim W.,Bennett E.J.,Huttlin E.L.,Guo A.,Li J.,Possemato A.,Sowa M.E.,Rad R.,Rush J.,and Comb M.J.,Harper J.W.,and Gygi S.P.,2011,Systematic and quantitative assessment of the ubiquitin-modified proteome,Molecular Cell,44(2):325-340
Kolas N.K.,Chapman J.R.,Nakada S.,Ylanko J.,Chahwan R.,Sweeney F.D.,Panier S.,Mendez M.,Wildenhain J.,Thomson T.M.,Pelletier L.,Jackson S.P.,and Durocher D.,2007,Orchestration of the DNA-damage response by the RNF8ubiquitin ligase,Science,318(5856):1637-1640
Kongsema M.,Zona S.,Karunarathna U.,and Cabrera E.,Man E.P.S.,Yao S.,Shibakawa A.,Khoo U.,Medema R.H.,Freire R.,and Lam E.W.,2016,RNF168 cooperates with RNF8 to mediate FOXM1 ubiquitination and degradation in breast cancer epirubicin treatment,Oncogenesis,5(8):e252
Lavin M.F.,2007,ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks,Oncogene,26(56):7749-7758
Lee H.J.,Ruan D.,He J.,and Chan C.H.,2016,Two-faced activity of RNF8:What“twists”it from a genome guardian to a cancer facilitator?Molecular and Cellular Oncology,3(6):e1242454
Li M.L.,and Greenberg R.A.,2012,Links between genome integrity and BRCA1 tumor suppression,Trends in Biochemical Sciences,37(10):418-424
Lilley C.E.,Chaurushiya M.S.,Boutell C.,Landry S.,Suh J.,Panier S.,Everett R.D.,Stewart G.S.,Durocher D.,and Weitzman M.D.,2010,A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses,EMBO J.,29(5):943-955
Luijsterburg M.S.,Acs K.,Ackermann L.,Wiegant W.W.,BekkerJensen S.,Larsen D.H.,and Dantuma,N.P.,2012,A new noncatalytic role for ubiquitin ligase RNF8 in unfolding higherorder chromatin structure,EMBO J.,31(11):2511-2527
Lukas J.,Lukas C.,and Bartek J.,2011,More than just a focus:The chromatin response to DNA damage and its role in genome integrity maintenance,Nature Cell Biology,13(10):1161-1169
Mailand N.,Bekker-Jensen S.,Faustrup H.,Melander F.,Bartek J.,Lukas C.,and Lukas J.,2007,RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins,Cell,131(5):887-900
Mattiroli F.,Vissers J.H.A.,Van D.W.J.,Ikpa P.,Citterio E.,Vermeulen W.,Marteijn J.A.,and Sixma T.K.,2012,RNF168ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling,Cell,150(6):1182-1195
Nair N.,Shoaib M.,and Sorensen C.S.,2017,Chromatin dynamics in genome stability:roles in suppressing endogenous DNAdamage and facilitating DNA repair,International Journal of Molecular Sciences,18(7):1486
Nakada S.,Tai I.,Panier S.,Al-Hakim A.,Iemura S.,and Juang Y.C.,O'Donnel L.,Kumakubo A.,Munro M.,Sicheri F.,Gingras A.,Natsume T.,Suda T.,and Durocher D.,2010,Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1,Nature,466(7309):941-946
Noon A.T.,and Goodarzi A.A.,2011,53BP1-mediated DNA double strand break repair insert bad pun here,DNA Repair,10(10):1071-1076
Panier S.,Ichijima Y.,Fradet-Turcotte A.,Leung C.C.Y.,Kaustov L.,Arrowsmith C.H.,and Durocher D.,2012,Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks,Molecular Cell,47(3):383-395
Poulsen M.,Lukas C.,Lukas J.,Bekker-Jensen S.,and Mailand N.,2012,Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks,J.Cell Biol.,197(2):189-199
Shire K.,Wong A.I.,Tatham M.H.,Anderson O.F.,Ripsman D.,Gulstene S.,Moffat J.,Hay R.T.,and Frappier L.,2016,Identification of RNF168 as a PML nuclear body regulator,J.,Cell Sci.,129(3):580-591
Stewart G.S.,Stankovic T.,Byrd P.J.,Wechsler T.,Miller E.S.,Huissoon A.,Drayson M.T.,West S.C.,Elledge S.J.,and Taylor A.M.R.,2007,RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling,Proc.Natl.Acad.Sci.USA,104(43):16910-16915
Thorslund T.,Ripplinger A.,Hoffmann S.,Wild T.,Uckelmann M.,Villumsen B.,Narita T.,Sixma T.K.,Choudhary C.,Bekker-Jensen S.,and Mailand N.,2015,Histone H1 couples initiation and amplification of ubiquitin signalling after DNAdamage,Nature,527(7578):389-393
Wang S.,Luo H.,Wang C.,Sun H.,Sun G.,Sun N.,Zeng K.,Song H.,Zou R.,Zhou T.,Cong R.,Liu W.,Yang L.,Li D.,Zhou X.,Zhong X.,Lin L.,Jiao J.,Yan G.,Wang X.,Min X.,Cao L.,and Zhao Y.,2017,RNF8 identified as a co-activator of estrogen receptorαpromotes cell growth in breast cancer,Biochimica et Biophysica Acta(BBA)-Molecular Basis of Disease,1863(6):1615-1628
Wang X.,Wei X.F.,and Zhang H.Q.,2015,Role of protein ubiq uitination and its functional importance,Zhongguo Kexue(Scientia Sinica Vitae),45:1074-1082(王翔,魏潇凡,张宏权,2015,泛素化的功能及其意义,中国科学,45:1074-1082)
Wu J.,Liu C.,Chen J.,and Yu X.,2012,RAP80 protein is important for genomic stability and is required for stabilizing BR-CA1-A complex at DNA damage sites in Vivo,J.Biol.Chem.,287(27):22919-22926
Xu Y.,Sun Y.,Jiang X.,Ayrapetov M.K.,Moskwa P.,and Yang S.,Weinstock D.M.,and Price B.D.,2010,The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair,J.Cell Biol.,191(1):31-43
Zhang X.Q.,2014,Structural and functional research of RINGdomain of RNF 168,Dissertation for Ph.D.,University of Science and Technology of China,Supervisor:Zang J.Y.,pp.21-38(张小秦,2014,泛素连接酶RNF168RING结构域的结构和功能研究,博士学位论文,中国科技大学,导师:藏建业,pp.21-38)
Bartocci C.,and Denchi E.L.,2013,Put a RING on it:regulation and inhibition of RNF8 and RNF168 RING finger E3 ligases at DNA damage sites,Frontiers in Genetics,4(128):1-12
Bekker-Jensen S.,Danielsen J.R.,Fugger K.,Gromova I.,Nerstedt A.,Lukas C.,and Mail N.,2010,HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes,Nature Cell Biology,(12):80-86
Botuyan M.V.,Lee J.,Ward I.M.,Kim J.E.,Thompson J.R.,Chen J.,and Mer G.,2006,Structural basis for the methylation statespecific recognition of histone H4-K20 by 53BP1 and Crb2in DNA repair,Cell,127(7):1361-1373
Doil C.,Mailand N.,Bekker-Jensen S.,Menard P.,Larsen D.H.,Pepperkok R.,Ellenberg J.,Panier S.,Durocher D.,Bartek J.,Lukas J.,and Lukas C.,2009,RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins,Cell,136(3):435-446
Fradet-Turcotte A.,Canny M.D.,and Escribano-Diaz C.,2013,53BP1 is a reader of the DNA-damage-induced H2A Lys 15ubiquitin mark,Nature,499(7456):50-54
Gudjonsson T.,Altmeyer M.,Savic V.,Toledo L.,Dinant C.,and Gr尴fte M.,2012,TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes,Cell,150(4):697-709
Guturi K.K.N.,Bohgaki M.,Bohgaki T.,Srikumar T.,Ng D.,Kumareswaran R.,Ghamrashi S.E.,Jeon J.,Patel P.,Eldin M.S.,Bristow R.,Cheung P.,Stewart G.S.,Raught B.,Hakem A.,and Hakem R.,2016,RNF168 and USP10 regulate topoisomerase IIαfunction via opposing effects on its ubiquitylation,Nature Communications,7(12638):1-13
Huen M.S.,Grant R.,Manke I.,Minn K.,Yu X.,Yaffe M.B.,and Chen J.,2007,RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly,Cell,131(5):901-914
Jackson S.P.,and Bartek J.,2009,The DNA-damage response in human biology and disease,Nature,461(7267):1071-1078
Jackson S.P.,and Durocher D.,2013,Regulation of DNA damage responses by ubiquitin and SUMO,Molecular Cell,49(5):795-807
Jeggo P.A.,and Lobrich M.,2007,DNA double-strand breaks:their cellular and clinical impact,Oncogene,26(56):7717-7719
Joo H.Y.,Zhai L.,Yang C.Y.,Nie S.Y.,Erdjument-Bromage H.,and Tempst P.,2007,Regulation of cell cycle progression and gene expression by H2A deubiquitination,Nature,449:1068-1072
Kakarougkas A.,and Jeggo P.A.,2014,DNA DSB repair pathway choice:an orchestrated handover mechanism,The British Journal of Radiology,87(1035):20130685
Kim W.,Bennett E.J.,Huttlin E.L.,Guo A.,Li J.,Possemato A.,Sowa M.E.,Rad R.,Rush J.,and Comb M.J.,Harper J.W.,and Gygi S.P.,2011,Systematic and quantitative assessment of the ubiquitin-modified proteome,Molecular Cell,44(2):325-340
Kolas N.K.,Chapman J.R.,Nakada S.,Ylanko J.,Chahwan R.,Sweeney F.D.,Panier S.,Mendez M.,Wildenhain J.,Thomson T.M.,Pelletier L.,Jackson S.P.,and Durocher D.,2007,Orchestration of the DNA-damage response by the RNF8ubiquitin ligase,Science,318(5856):1637-1640
Kongsema M.,Zona S.,Karunarathna U.,and Cabrera E.,Man E.P.S.,Yao S.,Shibakawa A.,Khoo U.,Medema R.H.,Freire R.,and Lam E.W.,2016,RNF168 cooperates with RNF8 to mediate FOXM1 ubiquitination and degradation in breast cancer epirubicin treatment,Oncogenesis,5(8):e252
Lavin M.F.,2007,ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks,Oncogene,26(56):7749-7758
Lee H.J.,Ruan D.,He J.,and Chan C.H.,2016,Two-faced activity of RNF8:What“twists”it from a genome guardian to a cancer facilitator?Molecular and Cellular Oncology,3(6):e1242454
Li M.L.,and Greenberg R.A.,2012,Links between genome integrity and BRCA1 tumor suppression,Trends in Biochemical Sciences,37(10):418-424
Lilley C.E.,Chaurushiya M.S.,Boutell C.,Landry S.,Suh J.,Panier S.,Everett R.D.,Stewart G.S.,Durocher D.,and Weitzman M.D.,2010,A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses,EMBO J.,29(5):943-955
Luijsterburg M.S.,Acs K.,Ackermann L.,Wiegant W.W.,BekkerJensen S.,Larsen D.H.,and Dantuma,N.P.,2012,A new noncatalytic role for ubiquitin ligase RNF8 in unfolding higherorder chromatin structure,EMBO J.,31(11):2511-2527
Lukas J.,Lukas C.,and Bartek J.,2011,More than just a focus:The chromatin response to DNA damage and its role in genome integrity maintenance,Nature Cell Biology,13(10):1161-1169
Mailand N.,Bekker-Jensen S.,Faustrup H.,Melander F.,Bartek J.,Lukas C.,and Lukas J.,2007,RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins,Cell,131(5):887-900
Mattiroli F.,Vissers J.H.A.,Van D.W.J.,Ikpa P.,Citterio E.,Vermeulen W.,Marteijn J.A.,and Sixma T.K.,2012,RNF168ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling,Cell,150(6):1182-1195
Nair N.,Shoaib M.,and Sorensen C.S.,2017,Chromatin dynamics in genome stability:roles in suppressing endogenous DNAdamage and facilitating DNA repair,International Journal of Molecular Sciences,18(7):1486
Nakada S.,Tai I.,Panier S.,Al-Hakim A.,Iemura S.,and Juang Y.C.,O'Donnel L.,Kumakubo A.,Munro M.,Sicheri F.,Gingras A.,Natsume T.,Suda T.,and Durocher D.,2010,Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1,Nature,466(7309):941-946
Noon A.T.,and Goodarzi A.A.,2011,53BP1-mediated DNA double strand break repair insert bad pun here,DNA Repair,10(10):1071-1076
Panier S.,Ichijima Y.,Fradet-Turcotte A.,Leung C.C.Y.,Kaustov L.,Arrowsmith C.H.,and Durocher D.,2012,Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks,Molecular Cell,47(3):383-395
Poulsen M.,Lukas C.,Lukas J.,Bekker-Jensen S.,and Mailand N.,2012,Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks,J.Cell Biol.,197(2):189-199
Shire K.,Wong A.I.,Tatham M.H.,Anderson O.F.,Ripsman D.,Gulstene S.,Moffat J.,Hay R.T.,and Frappier L.,2016,Identification of RNF168 as a PML nuclear body regulator,J.,Cell Sci.,129(3):580-591
Stewart G.S.,Stankovic T.,Byrd P.J.,Wechsler T.,Miller E.S.,Huissoon A.,Drayson M.T.,West S.C.,Elledge S.J.,and Taylor A.M.R.,2007,RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling,Proc.Natl.Acad.Sci.USA,104(43):16910-16915
Thorslund T.,Ripplinger A.,Hoffmann S.,Wild T.,Uckelmann M.,Villumsen B.,Narita T.,Sixma T.K.,Choudhary C.,Bekker-Jensen S.,and Mailand N.,2015,Histone H1 couples initiation and amplification of ubiquitin signalling after DNAdamage,Nature,527(7578):389-393
Wang S.,Luo H.,Wang C.,Sun H.,Sun G.,Sun N.,Zeng K.,Song H.,Zou R.,Zhou T.,Cong R.,Liu W.,Yang L.,Li D.,Zhou X.,Zhong X.,Lin L.,Jiao J.,Yan G.,Wang X.,Min X.,Cao L.,and Zhao Y.,2017,RNF8 identified as a co-activator of estrogen receptorαpromotes cell growth in breast cancer,Biochimica et Biophysica Acta(BBA)-Molecular Basis of Disease,1863(6):1615-1628
Wang X.,Wei X.F.,and Zhang H.Q.,2015,Role of protein ubiq uitination and its functional importance,Zhongguo Kexue(Scientia Sinica Vitae),45:1074-1082(王翔,魏潇凡,张宏权,2015,泛素化的功能及其意义,中国科学,45:1074-1082)
Wu J.,Liu C.,Chen J.,and Yu X.,2012,RAP80 protein is important for genomic stability and is required for stabilizing BR-CA1-A complex at DNA damage sites in Vivo,J.Biol.Chem.,287(27):22919-22926
Xu Y.,Sun Y.,Jiang X.,Ayrapetov M.K.,Moskwa P.,and Yang S.,Weinstock D.M.,and Price B.D.,2010,The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair,J.Cell Biol.,191(1):31-43
Zhang X.Q.,2014,Structural and functional research of RINGdomain of RNF 168,Dissertation for Ph.D.,University of Science and Technology of China,Supervisor:Zang J.Y.,pp.21-38(张小秦,2014,泛素连接酶RNF168RING结构域的结构和功能研究,博士学位论文,中国科技大学,导师:藏建业,pp.21-38)