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中图分类号:Q71;Q52

文献标识码:A

文章编号:1007-4368(2023)01-113-09

DOI:10.7655/NYDXBNS20230119

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目录contents

    摘要

    p53结合蛋白1(p53-binding protein 1,53BP1)在协调DNA双链断裂(DNA double strand break,DSB)修复途径选择中起关键作用。关于53BP1募集到受损染色质中的基本分子机制,以及组蛋白修饰在53BP1募集中的作用,已有大量文献报道了全新的见解。H4K20me2 和 H2AK15ub 是决定 53BP1 能否结合到受损染色质中的关键因素。最新证据表明,H3K18、 H3K56乙酰化及H4K16乙酰化/甲基化对53BP1募集均有一定程度的影响。文章对53BP1的结构、53BP1募集的分子机制和组蛋白修饰在调节53BP1募集中的作用进行了综述,并为癌症治疗提供新的思路。

    Abstract

    p53 binding protein 1(53BP1)plays a crucial role in coordinating the selection of DNA double - strand break(DSB) repair pathway. Underlying molecular mechanisms of 53BP1 recruitment to damaged chromatin and the function of histone modifications in that process have been reported in extensive literature. H4K20me2 and H2AK15ub are the key factors that determine whether 53BP1 can bind to damaged chromatin. Recent evidence suggests that the acetylation of H3K18 and H3K56,as well as the acetylation/methylation of H4K16,have a certain effect on 53BP1 recruitment. This article reviews the structure of 53BP1,the molecular mechanism of 53BP1 recruitment,and the role of histone modifications in regulating 53BP1 recruitment,and provides new ideas for cancer therapy.

  • DNA 是细胞生命周期中最重要的生物大分子。在真核细胞中,DNA浓缩成染色质[1]。染色质的核心单位是核小体,它由146 bp的DNA缠绕组蛋白八聚体1.75圈而形成[2]。组蛋白八聚体由组蛋白 H2A、H2B、H3和H4各2个分子构成,它是真核细胞染色体中核小体的核心颗粒[3]。DNA在代谢的过程中,会受到外源性损伤因子和内源性DNA损伤的影响,如电离辐射、紫外线辐射、化学试剂、DNA 去嘌呤化等。一旦DNA发生损伤而不能被及时修复时,细胞将发生衰老、自噬和凋亡[4]

  • DSB 是引发基因组不稳定的最主要因素,而 DSB修复途径对基因组完整性的维持至关重要[5]。真核生物修复 DSB 主要有两种途径:同源重组 (homologous recombination,HR)修复和非同源末端连接(non ⁃ homologous end ⁃ joining,NHEJ)修复。 NHEJ修复在G1期占主导地位,而HR修复在S、G2 期更具优势[6]。在细胞周期的不同时期,DNA损伤信号引起的组蛋白修饰不同。而不同的组蛋白修饰将决定p53结合蛋白1(p53⁃binding protein 1,53BP1)或乳腺癌1易感蛋白(breast cancer type1 susceptibility protein,BRCA1)是否结合到受损的染色质中。在G1 期,53BP1结合到DNA末端,保护DNA末端免受核酸酶切割处理,这有利于NHEJ修复途径的顺利进行。而在S、G2期,BRCA1结合到DSB位点并启动末端切除,从而推动HR修复的进行[7]。确定组蛋白修饰如何调节这两个过程,对于理解DSB修复过程和寻找新的癌症治疗方法至关重要。

  • 53BP1 在 DSB 位点的募集主要受几种修复调节因子的影响,如共济失调毛细血管扩张突变 (ataxia⁃telangiectasia mutated,ATM)和RAP1相互作用因子1(RAP1⁃interacting factor 1,RIF1)[8]。53BP1 与染色质的结合被认为主要受几个组蛋白修饰的调节。例如,53BP1的Tudor结构域识别H4K20me2 过程,是 53BP1 结合染色质最关键的步骤[8]。 H2AK15ub 增强了 53BP1 与受损染色质的结合,其泛素化过程是由 E3 连接酶 RNF8 和 RNF168 催化的[9]。然而,参与53BP1与染色质结合的组蛋白修饰远不止这两种。通过单独或者联合抑制组蛋白的修饰,人们发现H3K18、H3K56、H4K16乙酰化以及 H4K16 甲基化也参与调节 53BP1 与染色质的结合[810-11]。因此,本文将重点阐述53BP1募集分子机制和组蛋白修饰对53BP1结合染色质的影响。

  • 1 53BP1的结构

  • 53BP1 由 1 972 个氨基酸组成,其 N 端富含丝/ 苏氨酸⁃谷氨酰胺,具有ATM、RIF1、Pax反活化域相互作用蛋白(pax transactivation ⁃ domain interacting protein,PTIP)以及细胞周期依赖性激酶(cyclin⁃ dependent kinases,CDK)等重要激酶的磷酸化调控位点[12]。foci 形成区(foci⁃forming region,FFR) 是 53BP1 募集的重要结构域。FFR 包括寡聚域 (oligomerization domain,OD)、串联的 Tudor 结构域以及泛素化依赖的基序(ubiquitination dependent recruitment,UDR)[13-15]。C 端由两个串联的 BRCA1 羧基末端(BRCA1 carboxyl⁃terminal,BRCT)结构域组成,是53BP1和其他蛋白质相互作用的区域[16]

  • 2 53BP1募集的分子机制

  • 2.1 53BP1乙酰化和磷酸化

  • 53BP1的翻译后修饰可决定其能否募集到DSB 位点,而乙酰化则是最常见的修饰之一。经过质谱分析,CREB结合蛋白(CREB binding protein,CBP)可以促使 53BP1 的重要结构域 Tudor 和 UDR 的赖氨酸 1626/1628残基发生乙酰化。53BP1赖氨酸1626/1628 残基乙酰化后,53BP1与核小体之间的相互作用被阻碍。当发生DSB时,53BP1的乙酰化过程受到调控。组蛋白去乙酰化酶 2(histone deacetylase,HDAC2) 是使53BP1去乙酰化的关键因子[15]。在HDAC2的作用下,53BP1才被允许募集到受损的染色质中。

  • 53BP1 在不同细胞周期进程中发生不同的修饰。在有丝分裂过程中,53BP1的UDR基序磷酸化后,可避免53BP1过早地募集到染色质中。在有丝分裂早期和中期,53BP1的UDR基序的苏氨酸1609 和丝氨酸1618残基处于磷酸化状态[17]。已有相关文献表明,UDR 基序磷酸化是由 CDK1 和 polo 样激酶 1(polo like kinase1,PLK1)联合介导的[18-19]。在有丝分裂后期和末期,蛋白磷酸酶 4 的催化亚基 (protein phosphatase4 catalytic subunit,PP4C)发生磷酸化。随后,PP4C使UDR基序丝氨酸1618残基去磷酸化[1720]。当细胞进入G1期,53BP1去磷酸化彻底完成,并恢复其在DNA损伤反应(DNA damage response,DDR)中的功能。

  • 2.2 53BP1募集过程

  • 在 DNA 发生损伤前,53BP1 的 Tudor 结构域被 Tudor 相互作用修复调节因子(Tudor ⁃interacting repair regulator,TIRR)掩盖[21]。TIRR 是 53BP1 募集的抑制剂,它调控 53BP1 在 DNA 损伤前后的募集[21-22]。由于 Tudor 结构域与 TIRR 相结合,这阻碍了 53BP1 与 H4K20me2 的结合[23-27]。此外,组蛋白 H3K18、H3K56 和 H4K16 均处于乙酰化状态,共同阻止 53BP1 与染色质的结合[81028]。组蛋白 H4K20me2与53BP1的结合位点被甲基赖氨酸结合蛋白1(methyl⁃Lysine binding protein 1,L3MBTL1)和赖氨酸去甲基酶4A(lysine demethylase4a,KDM4A) 掩盖[29-30]。当DNA发生损伤时,由减数分裂重组蛋白 11(meiotic recombination 11,MRE11)、DNA 损伤修复蛋白 50(DNA repair protein 50,RAD50)、尼梅亨断裂综合征基因1(Nijmegen breakage syndrome1, NBS1)组成的MRN复合体和DNA依赖性蛋白激酶 (DNA⁃dependent protein kinase,DNA⁃PK)共同识别DSB 末端,并激活 ATM[31]。ATM 介导 53BP1 的磷酸化,并与 RIF1 共同促进 53BP1⁃TIRR 复合体的解离[22-23]。同时,ATM迅速磷酸化组蛋白H2A的丝氨酸139残基,使之转变为γH2AX。γH2AX持续放大损伤信号,并通过蛋白质相互作用网络招募DNA 损伤检查点蛋白调节子 1(mediator of DNA damage checkpoint protein 1,MDC1)[32]。此外,ATM 还激活了检查点激酶 1(checkpoint kinase1,CHK1)。 CHK1 使抗沉默因子 1A(anti⁃silencing function 1a, ASF1A)发生磷酸化[33]。磷酸化的 ASF1A 与 MDC1 的相互作用增强了MDC1与ATM的相互作用,继而使MDC1⁃RNF8⁃RNF168⁃组蛋白泛素化⁃53BP1轴的信号级联反应激活[34] (图1)。MDC1促使泛素连接酶 RNF8 和 RNF168 募集到受损染色质[35]。SIRT3 以 RNF8 依赖的方式被募集到染色质中[10]。SIRT7 以聚(ADP⁃核糖)聚合酶 1[poly(ADP⁃ribose)poly⁃ merase1,PARP1]依赖的方式被募集到受损染色质中[36]。SIRT3和SIRT7分别介导H3K56和H3K18去乙酰化。HDAC 介导 H4K16ac 去乙酰化。随后, GLP以ATM依赖的方式募集到受损染色质中,介导 H4K16甲基化[37]。H4K16me1提高了53BP1的Tudor 结构域对H4K20me2的亲和力[8]。同时,H4K20me2 以依赖 RNF8 的方式与 L3MBTL1 和 KDM4A 解离,并暴露其识别 53BP1 的结合位点[38-39]。RNF8 和 RNF168共同促使H2AK15泛素化为H2AK15ub[40]。 53BP1 通过其 UDR 基序和 Tudor 结构域分别与 H2AK15ub和H4K20me2结合[41-42] (图2)。53BP1从核质转移到受损染色质中,并与下游因子相互作用。RIF1被募集到DSB位点,与53BP1的N端相互作用[43]。REV7(DNA 聚合酶ζ的小亚基,又称为 MAD2L2)则以53BP1、RIF1和ATM依赖的方式募集到染色质中[44]。53BP1⁃RIF1⁃REV7 共同保护 DSB 末端免受羧基末端结合蛋白相互作用蛋白(CtBP interacting protein,CtIP)的切割处理[45]

  • 图1 53BP1募集的基本分子机制

  • Figure1 The basic molecular mechanism of 53BP1 recruitment

  • 图2 组蛋白在DSB前后的修饰

  • Figure2 Modification of histone before and after DSB

  • 3 参与53BP1募集的组蛋白及其作用机制

  • 3.1 H2AK15

  • 组蛋白H2AK15ub是由53BP1选择性识别的[46]。 H2AK15泛素化是决定53BP1的UDR基序能否识别 H2AK15ub最重要的步骤。当53BP1结合H2AK15ub 后,53BP1 才能及时有效地募集到 DSB 位点[47]。 H2AK15 的泛素化依赖于泛素连接酶 RNF8 和 RNF168[40]。然而,最新研究表明,H2AK15ub 不完全在53BP1募集中发挥作用。在发生DSB时,细胞中发生一系列蛋白质磷酸化事件,其中包括部分泛素的苏氨酸12残基磷酸化(pUbT12)事件。泛素苏氨酸 12 残基发生磷酸化在 H2AK15 泛素化和 DDR 调节中有着意想不到的作用。在 RNF168 的催化下,磷酸化的泛素苏氨酸12残基促使H2AK15发生泛素化产生 H2AKpubT12。而苏氨酸 12 残基位于 53BP1 和 H2AK15ub 复合体相互识别的界面,苏氨酸 12 磷酸化极大地破坏了 53BP1 和 H2AK15ub 相互作用的稳定性[41]。H2AKpubT12对53BP1的最直接影响是53BP1不能识别含有H2AKpubT12的染色质区域,取而代之的是该染色质区域被 RNF169、 DNA 损伤修复蛋白 51(DNA repair protein 51, RAD51)以及 BRCA1 识别。过多的泛素苏氨酸 12 残基发生磷酸化还可能不受控制地刺激RNF169的激活[41]。RNF169 是 RNF168 的同源物[48],RNF169 通过对泛素结构的竞争来限制RNF168介导的信号转导,最终也会抑制53BP1募集到DSB中[40]。由此可见,H2AK15ub可能通过泛素苏氨酸12残基的磷酸化和去磷酸化来调节53BP1募集。

  • 3.2 H4K20

  • 作为在 53BP1 募集中最关键的组蛋白之一, H4K20 是否甲基化可以决定 G1、G2 和 S 期修复途径的选择[49]。H4K20me2 确保 53BP1⁃RIF1⁃REV7 复合物被募集到染色质中[50]。另外,组蛋白 H4K20 在未甲基化时促进53BP1移除和BRCA1募集[51]。在 G1期,H4K20me2在53BP1结合位点处于饱和水平,这促使53BP1⁃RIF1⁃REV7复合物募集到DSB,并促使BRCA1从DSB移除。在S、G2期,H4K20me2的浓度下降使得53BP1⁃RIF1⁃REV7复合物移除。随后,未甲基化状态的组蛋白 H4K20浓度相对增加,并促使 BRCA1 募集到 DSB[52]。组蛋白 H4K20 代表修复途径的开关,它确保NHEJ修复在G1期占主导地位,而 HR 修复在 S、G2 期更具优势[6]。总而言之, H4K20me2 对于53BP1在染色质的募集是非常重要的[47]

  • 正常情况下,即使 H4K20me2 的浓度处于饱和状态也无法识别 53BP1,其原因可从 H4K20me2 和 53BP1 这两个角度进行阐释。首先,53BP1 无法识别 H4K20me2 是因为正常状态下,H4K20me2 被埋藏于染色质中。H4K20me2是由赖氨酸甲基转移酶 5A(lysine methyltransferase5A,KMT5A)和组蛋白甲基转移酶(suppressor of variegation 4 ⁃ 20 homolog, Suv4⁃20H)协同作用而产生。由KMT5A催化的第一次甲基化产生的H4K20me1促进了Suv4⁃20H募集,而 Suv4⁃20H 的募集又催化 H4K20me1 发生第二次甲基化[53]。经过两次甲基化的组蛋白 H4K20 将一直埋藏于染色质中,直到发生 DSB 时才暴露出来[54]。H4K20me2 一直埋藏在染色质中无法被 53BP1识别,是因为其结合位点被各种结合蛋白覆盖,其中最关键的结合蛋白是 L3MBTL1[29]和 KDM4A[30],KDM4A、L3MBTL1 共同竞争 53BP1 和 H4K20me2 的结合位点,阻碍了 53BP1 识别 H4K20me2。其次,53BP1无法识别H4K20me2的另一个原因是53BP1被TIRR掩盖。TIRR抑制53BP1 与 H4K20me2 之间的相互作用,它掩盖了 53BP1 的 Tudor结构域[24]。总而言之,L3MBTL1和TIRR通过阻止 H4K20me2 与 53BP1 的 Tudor 结构域之间的相互作用来抑制 53BP1 对 DSB 的募集。在发生 DSB 时,ATM促进53BP1⁃TIRR复合物解离,使得53BP1 能够识别 H4K20me2 [2327]。ATM 与 MDC1 的结合使 MDC1⁃RNF8⁃RNF168⁃组蛋白泛素化⁃53BP1轴的信号级联反应激活。含缬氨酸蛋白(valosin⁃containing protein,VCP)以 RNF8 和泛素依赖的方式募集到 DSB中,并介导L3MBTL1与H4K20me2分离[38]。同时,KDM4A 被蛋白酶体以 RNF8 依赖的方式降解,这些都是53BP1与H4K20me2结合的前提[39]。这些研究共同证明了 H4K20me2 如何以 RNF8/RNF168 依赖的方式与53BP1结合。

  • 组蛋白H2AK15的泛素化和H4K20的甲基化过程在 DDR 中联系紧密。相关文献表明,RNF8 和 RNF168介导的H2AK15泛素化和KMT5A的募集存在一定关联。KMT5A在DDR中的活性是H4K20甲基化所必需的[38]。因此,RNF8、RNF168 和 KMT5A 在 53BP1 募集中的作用可以从两个方面解释。首先,作为组蛋白甲基转移酶,在特定的 DSB 位点 KMT5A可以诱导H4K20发生甲基化;其次,KMT5A 还是一种泛素化调节因子,可以增强 RNF168 介导的H2AK15泛素化[39]

  • 3.3 H3K18

  • 组蛋白 H3K18 以 SIRT7 介导的 H3K18ac 去乙酰化方式来调控 53BP1 募集[28]。SIRT7 属于 sirtuin 家族成员,这个家族的一个关键功能是调节和维持基因组的稳定性[55]。SIRT7以PARP1依赖的方式被招募到DSB 位点,并作用于组蛋白[28]。SIRT7可使组蛋白的启动子区域脱乙酰化,并选择性地去乙酰化H3K18ac的启动子区域[56]。SIRT7在表观遗传学上控制与线粒体生物发生、核糖体生物合成和DNA 损伤反应相关基因的转录[57]。SIRT7可以被DNA[58] 和 RNA[59] 激活,以水解组蛋白 H3K18 赖氨酸残基的乙酰基[60]。SIRT7 缺失使细胞对多种遗传毒物敏感[61-63]。SIRT7缺失还导致早衰以及胚胎存活率降低,这与基因修复缺陷有关[11]。在色氨酸2,3⁃双加氧酶(tryptophan 2,3⁃dioxygenase,TDO)活性被抑制的情况下,使用双氯乙基亚硝脲(bis⁃chloroethyl⁃ nitrosourea,BCNU)诱导胶质母细胞瘤细胞发生DSB 后,细胞表现出γH2AX信号增强和53BP1向染色质募集缺陷。TDO抑制减少了SIRT7脱乙酰酶在染色质中的募集,从而增加了组蛋白H3K18乙酰化—— 这是阻止53BP1募集到DSB位点的关键标志[64]。但是这个新的调节途径还没确定 53BP1 是如何与 H3K18相互作用的。目前,已有研究表明,H3K18ac 并没有通过影响H4K20me2、H2AK15ub与53BP1的结合来阻碍53BP1募集[28]

  • 3.4 H3K56

  • 组蛋白H3K56位于核小体的DNA进出位点,其乙酰化与DNA损伤后的转录和细胞存活等重要细胞功能相关[65-66]。在发生DSB时,RNF8介导SIRT3 定位于受损染色质中,并与53BP1共同定位[10]。随后,SIRT3介导H3K56ac去乙酰化,并促使53BP1募集到受损染色质中[10]。由于SIRT3和组蛋白H3K56 在53BP1募集中的稳定作用,细胞在遗传毒性应激下依然能够稳定地存活[67-68]。目前,尚未阐明53BP1 是否通过特定的结构域特异性识别H3K56。

  • 3.5 H4K16

  • H4K16ac是由Tat相互作用蛋白60(Tat interac⁃ tive protein 60,Tip60)乙酰基转移酶复合物催化产生的[69-70],它通过破坏 H4K16 和 Tudor 结构域之间的盐桥来减弱53BP1与H4K20me2的结合[5471]。相反,H4K16ac 去乙酰化则增强 53BP1 与 H4K20me2 结合以及 53BP1 foci 形成[54]。相关文献解释了 Tip60如何调节组蛋白的修饰和53BP1募集。在S、 G2期中,HR修复途径的激活依赖于BRCA1、53BP1与关键相互作用伙伴的结合[72]。在G1期,H4K16的乙酰化水平随DNA损伤程度变化。当发生DSB时, HDAC催化H4K16ac加速去乙酰化[71]。在S、G2期, Tip60 促使 H4K16 发生乙酰化,使得 53BP1 在 DSB 中的积累减少[73]。另外,Tip60在调节53BP1募集中除了调节H4K16乙酰化,还能通过乙酰化H2AK15 来阻止H2AK15泛素化[74]。相反,由RNF168介导的 H2AK15泛素化过程则抑制Tip60对H4K16乙酰化作用[74]。总之,H2AK15 的泛素化或乙酰化以及 Tip60 介导的组蛋白 H4K16 乙酰化过程相互影响,共同确保53BP1在正确的时期募集到染色质中。

  • 最近一项研究表明组蛋白 H4K16me1 也参与 53BP1的募集。H4K16甲基化主要受GLP调控。抑制GLP可阻止DNA修复进程,这可能是由于GLP可以抑制相关修复因子的募集。例如,通过抑制GLP 可减弱BRCA1募集从而抑制HR 修复[75-76]。然而,也有人报道,抑制GLP使NHEJ修复效率降低,而并不影响HR修复[77]。这是因为GLP被抑制后,53BP1 募集也受影响[8]。GLP调控的53BP1募集可能主要来自于 H4K16me1 和 53BP1 之间的相互作用。在 DDR 中,H4K16me1 水平与 H4K16ac 水平表现出相反的变化[8]。H4K16的赖氨酸残基甲基化与乙酰化相互竞争,H4K16甲基化水平增加可以抑制H4K16 乙酰化,从而确保53BP1募集。GLP除了可以调节 H4K16的甲基化,还可以通过介导MDC1甲基化来促进 53BP1 募集[3778]。MDC1 是 53BP1 在 DSB 位点积累所必需的。当发生DSB时,GLP以ATM依赖的方式被招募到受损染色质中[78]。随后,GLP介导的 MDC1甲基化可增强ATM的活性,从而扩大受损染色质周围的损伤信号。

  • 在发生 DSB 时,相对于 H4K16me1 水平的大幅增加,H4K20me2 水平的增加却相当有限[8]。这或许是因为 H4K20me2 在 DSB 发生前就已经大量积累在染色质中[54],所以H4K20me2在DNA发生损伤时不会增加太明显[879]。目前,已有相关研究介绍了 H4K16me1 和 H4K20me2 的抑制对 53BP1 foci 形成的影响。共同抑制 H4K16me1 [80] 和 H4K20me2 [81] 比单独抑制能更有效地抑制 53BP1 募集[8]。究其原因是 H4K16me1 提高了 53BP1 的 Tudor 结构域对 H4K20me2的亲和力。因此,H4K16me1与H4K20me2 可能联合调控53BP1募集[8]

  • 4 总结与展望

  • 在DSB修复相关研究领域中,53BP1作为细胞对 NHEJ 修复途径的重要调节因子,其在染色质中的募集成为当前的研究热点。多项研究证实53BP1 与染色质的结合主要受组蛋白修饰的调节,凸显了进一步研究组蛋白与53BP1作用机制的重要性。现有的研究大多关注修复调节因子对53BP1募集的影响。然而,组蛋白修饰在53BP1募集中发挥的作用也同样值得关注与进一步探索。本文综述了53BP1 结构、53BP1 募集分子机制以及组蛋白修饰在 53BP1募集中的作用机制,但仍有许多问题和重要的研究方向需要继续探索。组蛋白H3K18、H3K56 如何与53BP1相互作用以及它们是否影响53BP1识别 K2AK15ub、H4K20me2,尚有待深入研究。随着组蛋白修饰与53BP1募集的深度开发,可为癌症治疗提供更多选择。

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