WRAP53 β调控DNA损伤修复进展
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摘要
WRAP53β是一种具有WD40结构域的蛋白质,在维护卡哈尔体稳定、RNA剪接、端粒延伸等方面起着至关重要的作用.WRAP53β功能紊乱与先天性角化不良、肿瘤、进行性脊髓性肌萎缩、过早老化等疾病有关.近两年研究发现WRAP53β是DNA双链断裂修复(DSBs)的一个重要支架蛋白,它以一种依赖于ATM、H2AX、MDC1的方式被募集至损伤位点并磷酸化,其WD40结构域可募集泛素E3连接酶RNF8,将DSBs位点附近的组蛋白H2AX泛素化,促进下游修复因子的聚集,引起DNA损伤后的修复作用.为此,我们重点综述了现阶段WRAP53β在DNA损伤修复方面的具体作用及机制.
WRAP53 beta, a protein with a WD40 domain, plays an essential role in the maintenance of Cajal body stability, RNA splicing, and telomere elongation. WRAP53 β dysfunction is related to dyskeratosis congenita,tumor, progressive spinal muscular atrophy, premature aging and other diseases. Recent studies have found that WRAP53 β is an important scaffold protein essential for DNA double strand break repair(DSBs). It can be recruited to DNA damage sites in a H2 AX, ATM and MDC1-dependent manner and phosphorylated by ATM.Then the phosphorylated WRAP53 β recruits ubiquitin E3 ligase RNF8 through its WD40 domain leading to histone H2 AX ubiquitination, and further aggregation of downstream repair factors for DNA damage repair. In this review, we summarize the recent advances in the specific role and underlying mechanisms of WRAP53 β in the repair of DNA damages.
WRAP53 beta, a protein with a WD40 domain, plays an essential role in the maintenance of Cajal body stability, RNA splicing, and telomere elongation. WRAP53 β dysfunction is related to dyskeratosis congenita,tumor, progressive spinal muscular atrophy, premature aging and other diseases. Recent studies have found that WRAP53 β is an important scaffold protein essential for DNA double strand break repair(DSBs). It can be recruited to DNA damage sites in a H2 AX, ATM and MDC1-dependent manner and phosphorylated by ATM.Then the phosphorylated WRAP53 β recruits ubiquitin E3 ligase RNF8 through its WD40 domain leading to histone H2 AX ubiquitination, and further aggregation of downstream repair factors for DNA damage repair. In this review, we summarize the recent advances in the specific role and underlying mechanisms of WRAP53 β in the repair of DNA damages.
引文
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[24]d'Adda di Fagagna F,Teo S H,Jackson S P.Functional links between telomeres and proteins of the DNA-damage response.Genes Dev,2004,18(15):1781-1799
[25]Peuscher M H,Jacobs J J.DNA-damage response and repairactivities at uncapped telomeres depend on RNF8.Nat Cell Biol,2011,13(9):1139-1145
[26]Dimitrova N,Chen Y C,Spector D L,et al.53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility.Nature,2008,456(7221):524-528
[27]Wong J M,Kusdra L,Collins K.Subnuclear shuttling of human telomerase induced by transformation and DNA damage.Nat Cell Biol,2002,4(9):731-736
[28]Marianne Farnebo.Wrap53,a novel regulator of p53.Cell Cycle,2009,8(15):2343-2346
[29]Brault M E,Autexier C.Telomeric recombination induced by dysfunctional telomeres.Mol Biol Cell,2011,22(2):179-188
[30]Zhong Z H,Jiang W Q,Cesare A J,et al.Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres.J Biol Chem,2007,282(40):29314-29322
[2]Lee J H,Lee Y S,Jeong S A,et al.Catalytically active telomerase holoenzyme is assembled in the dense fibrillar component of the nucleolus during S phase.Histochem Cell Biol,2014,141(2):137-152
[3]Sun C K,Luo X B,Gou Y P,et al.TCAB1:a potential target for diagnosis and therapy of head and neck carcinomas.Mol Cancer.2014,13(1):180-191
[4]Rao X,Huang D,Sui X,et al.Overexpression of WRAP53 is associated with development and progression of esophageal squamous cell carcinoma.Plos One,2014,9(3):e91670
[5]Yuan X S,Cao L X,Hu Y J,et al.Clinical,cellular,and bioinformatic analyses reveal involvement of WRAP53overexpression in carcinogenesis of lung adenocarcinoma.Tumour Biol,2017,39(3):1010428317694309
[6]Mahmoudi S,Henriksson S,Farnebo L,et al.WRAP53 promotes cancer cell survival and is a potential target for cancer therapy.Cell Death Dis,2011,2:e114
[7]Garvin S,Tiefenbock K,Farnebo L,et al.Nuclear expression of WRAP53βis associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma.Oral Oncology,2015,51(1):24-30
[8]Hedstrom E,Pederiva C,Farnebo J,et al.Downregulation of the cancer susceptibility protein WRAP53βin epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome.Cell Death Dis,2015,6:e1892
[9]Rassoolzadeh H,Bohm S,Hedstrom E,et al.Overexpression of the scaffold WD40 protein WRAP53βenhances the repair of and cell survival from DNA double-strand breaks.Cell Death Dis,2016,7:e2267
[10]Henriksson S,Rassoolzadeh H,Hedstrom E,et al.The scaffold protein WRAP53βorchestrates the ubiquitin response critical for DNA double-strand break repair.Genes Dev,2014,28(24):2726-2738
[11]Mahmoudi S,Henriksson S,Weibrecht I,et al.WRAP53 is essential for Cajal body formation and for targeting the survival of motor neuron complex to Cajal bodies.Plos Biol,2010,8(11):e1000521
[12]Henriksson S,Farnebo M.On the road with WRAP53β:guardian of Cajal bodies and genome integrity.Front Genet,2015,6:91-100
[13]陆文昕,葛奕辰,肖丽英,等.WD40编码的P53 RNA反义转录子基因和蛋白及其功能.国际口腔医学杂志,2016,43(2):244-248Lu W X,Ge Y C,Xiao L Y,et al.Int J Stomatology,2016,43(2):244-248
[14]Tapia O,Bengoechea R,Palanca A,et al.Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy.Histochem Cell Biol,2012,137(5):657-667
[15]Tycowski K T,Shu M D,Kukoyi A,et al.A conserved WD40protein binds the Cajal body localization signal of sca RNP particles.Mol Cell,2009,34(1):47-57
[16]Rouse J,Jackson S P.Interfaces between the detection,signaling,and repair of DNA damage.Science,2002,297(5581):547-551
[17]Huen M S,Grant R,Manke I,et al.RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly.Cell,2007,131(5):901-914
[18]Durocher D,Jackson S P.DNA-PK,ATM and ATR as sensors of DNA damage:variations on a theme?Curr Opin Cell Biol,2001,13(2):225-231
[19]Coucoravas C,Dhanjal S,Henriksson S,et al.Phosphorylation of the Cajal body protein WRAP53βby ATM promotes its involvement in the DNA damage response.RNA Biol,2017,14(6):804-813
[20]Stucki M,Clapperton J A,Mohammad D,et al.MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.Cell,2005,123(7):1213-1226
[21]Velma V,Carrero Z I,Cosman A M,et al.Coilin inter-acts with Ku proteins and inhibits invitro non-homologous DNA end joining.FEBS Lett,2010,584(23):4735-4739
[22]Takaku M,Tsujita T,Horikoshi N,et al.Purification of the human SMN-GEMIN2 complex and assessment of its stimulation of RAD51-mediated DNA recombination reactions.Biochemistry,2011,50(32):6797-6805
[23]Galanty Y,Belotserkovskaya R,Coates J,et al.Mammalian SUMOE3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.Nature,2009,462(7275):935-939
[24]d'Adda di Fagagna F,Teo S H,Jackson S P.Functional links between telomeres and proteins of the DNA-damage response.Genes Dev,2004,18(15):1781-1799
[25]Peuscher M H,Jacobs J J.DNA-damage response and repairactivities at uncapped telomeres depend on RNF8.Nat Cell Biol,2011,13(9):1139-1145
[26]Dimitrova N,Chen Y C,Spector D L,et al.53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility.Nature,2008,456(7221):524-528
[27]Wong J M,Kusdra L,Collins K.Subnuclear shuttling of human telomerase induced by transformation and DNA damage.Nat Cell Biol,2002,4(9):731-736
[28]Marianne Farnebo.Wrap53,a novel regulator of p53.Cell Cycle,2009,8(15):2343-2346
[29]Brault M E,Autexier C.Telomeric recombination induced by dysfunctional telomeres.Mol Biol Cell,2011,22(2):179-188
[30]Zhong Z H,Jiang W Q,Cesare A J,et al.Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres.J Biol Chem,2007,282(40):29314-29322