PHF1在肿瘤DNA损伤修复中的作用

轻微的DNA损伤可启动损伤修复途径,严重的DNA损伤则会启动细胞休眠或凋亡途径。PHF1是PcG蛋白家族中的重要组分,参与复杂的生物学过程,包括DNA损伤修复、细胞休眠或凋亡、组蛋白翻译后修饰和染色体重排。本文主要对PHF1的结构、参与的信号通路、翻译后修饰及生物学功能做小结和展望,为PHF1进一步研究提供理论基础。     

RNF8/RNF168信号通路在DNA损伤修复中的作用

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。     

SUMO化修饰在DNA损伤响应中的作用

物理或化学等多种因素均可以引起DNA损伤。为维持机体基因组的稳定性,机体形成了精确完整的机制来修复损伤的／DNA。SUMO（smallubiquitin-relatedmodifier,SUMO）化修饰与其他蛋白翻译后修饰一样,具有多种生物学功能。近年来的研究表明,其在DNA损伤修复中也具有非常重要的作用。该文就DNA损伤修复、SUMO,96修饰系统及其二者关系的最新研究进展作了较为全面的介绍和总结。     

SUMO化修饰与DNA损伤修复

由于体内外因素的影响,DNA损伤是生物生命周期中的常见现象,如果得不到及时的修复,DNA损伤的积累将导致基因组的不稳定及染色质的异常,并可能导致肿瘤的发生发展。SUMO化修饰是体内一个重要的蛋白质翻译后修饰,越来越多的研究发现SUMO化修饰与多个参与DNA损伤反应、维持基因组稳定的蛋白质相关,有可能参与肿瘤的发生。本文将阐述SUMO化修饰与DNA损伤修复的关系。     

PCNA泛素化修饰对DNA损伤应答途径的调控

机体细胞在多种化学物质和内外环境不断攻击下会诱发DNA损伤。为了维持基因组的稳定性,细胞内拥有一系列完善而精确的细胞应答机制来保护基因组DNA的完整性。细胞首先通过DNA损伤检测点,然后通过一系列细胞信号转导通路,启动细胞周期阻滞,进而介导细胞修复或凋亡。大量研究表明泛素化作为一种重要的蛋白质翻译后修饰方式,参与调控了多种细胞生理过程。近期研究表明,DNA损伤导致复制应激可诱发PCNA的翻译后泛素化修饰,泛素化修饰的PCNA可能参与了多种DNA损伤应激过程,影响细胞选择不同的DNA损伤应答途径,导致细胞截然不同的转归。因此,更好地了解PCNA泛素化的作用及其影响DNA损伤应答通路可为我们更深入地了解人类细胞如何调控异常的DNA代谢过程和癌症的发生和发展机制提供依据。     

PCNA泛素化修饰对DNA损伤应答途径的调控

机体细胞在多种化学物质和内外环境不断攻击下会诱发DNA损伤。为了维持基因组的稳定性,细胞内拥有一系列完善而精确的细胞应答机制来保护基因组DNA的完整性。细胞首先通过DNA损伤检测点,然后通过一系列细胞信号转导通路,启动细胞周期阻滞,进而介导细胞修复或凋亡。大量研究表明泛素化作为一种重要的蛋白质翻译后修饰方式,参与调控了多种细胞生理过程。近期研究表明,DNA损伤导致复制应激可诱发PCNA的翻译后泛素化修饰,泛素化修饰的PCNA可能参与了多种DNA损伤应激过程,影响细胞选择不同的DNA损伤应答途径,导致细胞截然不同的转归。因此,更好地了解PCNA泛素化的作用及其影响DNA损伤应答通路可为我们更深入地了解人类细胞如何调控异常的DNA代谢过程和癌症的发生和发展机制提供依据。     

SUMO化修饰与DNA损伤修复

蛋白质的翻译后修饰在很大程度上决定了蛋白质的活性、细胞定位、稳定性及蛋白质之间的相互作用.而在DNA损伤修复过程中,通过调控不同修复蛋白的翻译后修饰来影响他们的活性及细胞定位,进而导致DNA损伤修复途径的不同和修复结果的差异.新近研究表明,蛋白质的SUMO化修饰在DNA损伤修复和基因组稳定性的维护方面发挥重要作用.本文将对SUMO化修饰对DNA损伤修复的调控的最新研究进展做一综述.     

受PCNA翻译后修饰调控的DNA损伤耐受机制

为了应对DNA损伤复制阻滞,增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)164位点的赖氨酸残基能够发生一系列的泛素化修饰并介导两种不用的损伤耐受机制,即DNA跨损伤合成(TLS)和无错耐受通路。目前,单泛素化的PCNA介导DNA跨损伤合成通路,而多泛素化的PCNA介导无错耐受通路这一观点已被普遍认可。另外,PCNA的164位点还能被泛素类似物小蛋白(SUMO)修饰,从而抑制DNA双链断裂重组。总结PCNA的翻译后修饰及其在DNA损伤应答过程中的作用机制,有助于我们了解PCNA在DNA损伤耐受机制中的中心作用。重点总结PCNA的翻译后修饰如何调控真核生物DNA损伤应答的不同途径。     

53BP1与DNA双链断裂损伤修复

DNA的精确复制和遗传对维持基因组稳定性有重要作用。DNA双链断裂损伤可能诱导细胞凋亡和染色质重排,在肿瘤的发生发展过程中发挥作用。53BP1是DNA双链断裂修复中的重要调节蛋白质之一,对调控损伤修复平衡和维持基因组稳定性起着重要作用。本文主要对53BP1的结构、生物学功能、信号通路、分子机制和翻译后修饰做一浅显的总结和展望,希望能为53BP1的深入研究提供一些理论基础。     

组蛋白翻译后修饰与DNA损伤响应蛋白招募的调控

组蛋白翻译后修饰是细胞DNA损伤早期应答反应的重要内涵,一方面是松弛、开放染色质结构的必要分子调节事件,以便DNA损伤响应蛋白能接近DNA损伤位点;另一方面直接参与DNA损伤修复蛋白招募过程的调控。综述了在DNA损伤信号激发下,发生的组蛋白主要修饰类型,异组蛋白H2AX、H2A.Z在DNA损伤部位与组蛋白置换,及其对DNA损伤响应蛋白招募的调节作用和机制。     

DNA修复的表观遗传学调控

表观遗传学信息的改变是导致人类肿瘤形成的重要因素之一．基因组的稳定性经常会受到DNA损伤的威胁．然而,高度致密的染色质结构却极大地妨碍了DNA修复的进行．因此,真核生物细胞中必须有一个精确的机制来克服染色质这一天然的屏障．其中,组蛋白的共价修饰和ATP-依赖的染色质重塑通过改变染色质的结构,对DNA修复进程起着关键的调控作用．介绍了DNA修复过程中,发生在表观遗传学方面的主要调控过程,特别阐述了在DNA双链断裂损伤应答和修复过程中,组蛋白修饰和染色质重塑方面最新的研究进展,并对今后的发展方向进行了讨论．     

The role of arginine methylation in the DNA damage response

Post-translational modifications are well-known modulators of DNA damage signaling and epigenetic gene expression. Protein arginine methylation is a covalent modification that results in the addition of methyl groups to the nitrogen atoms of the arginine side chains and is catalyzed by a family of protein arginine methyltransferases (PRMTs). In the past, arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine methylated proteins implicated in a variety of cellular processes including RNA metabolism, epigenetic regulation and DNA repair pathways. Herein, we discuss these recent advances, focusing on the role of PRMTs in DNA damage signaling and its importance for maintaining genomic stability.     

The multi-functionality of UHRF1: epigenome maintenance and preservation of genome integrity

During S phase, the cooperation between the macromolecular complexes regulating DNA synthesis, epigenetic information maintenance and DNA repair is advantageous for cells, as they can rapidly detect DNA damage and initiate the DNA damage response (DDR). UHRF1 is a fundamental epigenetic regulator; its ability to coordinate DNA methylation and histone code is unique across proteomes of different species. Recently, UHRF1’s role in DNA damage repair has been explored and recognized to be as important as its role in maintaining the epigenome. UHRF1 is a sensor for interstrand crosslinks and a determinant for the switch towards homologous recombination in the repair of double-strand breaks; its loss results in enhanced sensitivity to DNA damage. These functions are finely regulated by specific post-translational modifications and are mediated by the SRA domain, which binds to damaged DNA, and the RING domain. Here, we review recent studies on the role of UHRF1 in DDR focusing on how it recognizes DNA damage and cooperates with other proteins in its repair. We then discuss how UHRF1’s epigenetic abilities in reading and writing histone modifications, or its interactions with ncRNAs, could interlace with its role in DDR.     

An epigenetic code for DNA damage repair pathways?

Exposure of living cells to intracellular or external mutagens results in DNA damage. Accumulation of DNA damage can lead to serious consequences because of the deleterious mutation rate resulting in genomic instability, cellular senescence, and cell death. To counteract genotoxic stress, cells have developed several strategies to detect defects in DNA structure. The eukaryotic genomic DNA is packaged through histone and nonhistone proteins into a highly condensed structure termed chromatin. Therefore the cellular enzymatic machineries responsible for DNA replication, recombination, and repair must circumvent this natural barrier in order to gain access to the DNA. Several studies have demonstrated that histone/chromatin modifications such as acetylation, methylation, and phosphorylation play crucial roles in DNA repair processes. This review will summarize the recent data that suggest a regulatory role of the epigenetic code in DNA repair processes. We will mainly focus on different covalent reversible modifications of histones as an initial step in early response to DNA damage and subsequent DNA repair. Special focus on a potential epigenetic histone code for these processes will be given in the last section. We also discuss new technologies and strategies to elucidate the putative epigenetic code for each of the DNA repair processes discussed.     

Organization of DNA damage,excision repair,and mutagenesis in chromatin: A genomic perspective

Genomic DNA is constantly assaulted by both endogenous and exogenous damaging agents. The resulting DNA damage, if left unrepaired, can interfere with DNA replication and be converted into mutations. Genomic DNA is packaged into a highly compact yet dynamic chromatin structure, in order to fit into the limited space available in the nucleus of eukaryotic cells. This hierarchical chromatin organization serves as both the target of DNA damaging agents and the context for DNA repair enzymes. Biochemical studies have suggested that both the formation and repair of DNA damage are significantly modulated by chromatin. Our understanding of the impact of chromatin on damage and repair has been significantly enhanced by recent studies. We focus on the nucleosome, the primary building block of chromatin, and discuss how the intrinsic structural properties of nucleosomes, and their associated epigenetic modifications, affect damage formation and DNA repair, as well as subsequent mutagenesis in cancer.     

5-hydroxymethylcytosine in DNA repair: A new player or a red herring?

Active DNA demethylation performed by ten-eleven translocation (TET) enzymes produces 5-hydroxymethylcytosines, 5-formylcytosines, and 5-carboxylcytosines. Recent observations suggest that 5-hydroxymethylcytosine is a stable epigenetic mark rather than merely an intermediate of DNA demethylation. However, the clear functional role of this new epigenetic player is elusive. The contribution of 5-hydroxymethylation to DNA repair is being discussed currently. Recently, Jiang and colleagues have demonstrated that DNA damage response-activated ATR kinase phosphorylates TET3 in mammalian cells and promotes DNA demethylation and 5-hydroxymethylcytosine accumulation. Moreover, TET3 catalytic activity is important for proper DNA repair and cell survival. Here, we discuss recent studies on the potential role of 5-hydroxymethylation in DNA repair and genome integrity maintenance.     

Preserving genome integrity and function: the DNA damage response and histone modifications

Modulation of chromatin templates in response to cellular cues, including DNA damage, relies heavily on the post-translation modification of histones. Numerous types of histone modifications including phosphorylation, methylation, acetylation, and ubiquitylation occur on specific histone residues in response to DNA damage. These histone marks regulate both the structure and function of chromatin, allowing for the transition between chromatin states that function in undamaged condition to those that occur in the presence of DNA damage. Histone modifications play well-recognized roles in sensing, processing, and repairing damaged DNA to ensure the integrity of genetic information and cellular homeostasis. This review highlights our current understanding of histone modifications as they relate to DNA damage responses (DDRs) and their involvement in genome maintenance, including the potential targeting of histone modification regulators in cancer, a disease that exhibits both epigenetic dysregulation and intrinsic DNA damage.     

The role of DNA damage in laminopathy progeroid syndromes

Progeroid laminopathies are characterized by the abnormal processing of lamin A, the appearance of misshapen nuclei, and the accumulation and persistence of DNA damage. In the present article, I consider the contribution of defective DNA damage pathways to the pathology of progeroid laminopathies. Defects in DNA repair pathways appear to be caused by a combination of factors. These include abnormal epigenetic modifications of chromatin that are required to recruit DNA repair pathways to sites of DNA damage, abnormal recruitment of DNA excision repair proteins to sites of DNA double-strand breaks, and unrepairable ROS (reactive oxygen species)-induced DNA damage. At least two of these defective processes offer the potential for novel therapeutic approaches.