DNA损伤修复机制的研究进展

细胞遗传物质稳定性受自身与外界多种条件影响,可形成多种类型DNA损伤,如DNA烷基化、氧化、错配、成环、断裂、非典型结构等。这些受损DNA扰乱细胞稳态及动态平衡,引起基因突变、染色体畸形,甚至细胞和生物退化、老化、死亡等。人体通过识别DNA损伤位点,激活一系列生化通路,协调DNA复制与转录,使损伤DNA得以修复,维持机体相对独立、稳定。放射线引起肿瘤细胞DNA损伤同时,也启动DNA损伤应答,其中碱基切除修复、核苷酸切除修复、错配修复、双链断裂修复和跨损伤合成修复起关键作用,是细胞照射后DNA修复的主要途径,其功能异常可引起肿瘤放射敏感性差异。本文总结近年国内外DNA损伤修复方面的研究成果,着重阐述DNA损伤修复类型及分子机制,旨在促进读者对该领域重要意义的理解,为探索DNA损伤修复通路在肿瘤治疗中的应用提供理论基础。     

DNA损伤修复调控因子与肿瘤耐药的研究进展

DNA分子是生物细胞中易受辐射损伤的敏感分子,亦称靶分子.多种理化因素如紫外线、电离辐射、化学诱变剂等导致细胞DNA损伤,同时生物体内本身又存在修复体系.肿瘤细胞DNA修复能力与化疗药物敏感性密切相关.本文综述DNA损伤修复机制-碱基切除修复、核苷酸切除修复、错配修复、DNA双链断裂修复等研究进展以及与肿瘤耐药之间的联系.     

DNA修复基因预测非小细胞肺癌放化疗敏感性

化学药物和辐射所诱导的DNA损伤修复通路在肿瘤治疗疗效反应上扮演了重要的角色。肿瘤细胞DNA修复能力增强是肿瘤耐受放化疗的主要机制。DNA修复过程涉及许多基因, 这些基因在遗传学及表遗传学上的改变可影响DNA修复的能力,因此通过检测这些基因的单核苷酸多态性、甲基化状态以及基因的过表达来预测疗效。现综述近年来碱基切除修复基因、核苷酸剪切修复基因及双链断裂修复基因预测非小细胞肺癌放化疗疗效的研究进展。     

DNA修复基因预测非小细胞肺癌放化疗敏感性

化学药物和辐射所诱导的DNA损伤修复通路在肿瘤治疗疗效反应上扮演了重要的角色。肿瘤细胞DNA修复能力增强是肿瘤耐受放化疗的主要机制。DNA修复过程涉及许多基因，这些基因在遗传学及表遗传学上的改变可影响DNA修复的能力，因此通过检测这些基因的单核苷酸多态性、甲基化状态以及基因的过表达来预测疗效。现综述近年来碱基切除修复基因、核苷酸剪切修复基因及双链断裂修复基因预测非小细胞肺癌放化疗疗效的研究进展。     

DNA修复基因预测非小细胞肺癌化疗敏感性研究进展

人类细胞具有一系列DNA修复系统，以防御体内和体外因素引起的不同类型的DNA损伤，保持基因组的完整性。研究表明DNA修复能力低可能与个体肿瘤易感性密切相关，然而在肿瘤的治疗过程中，DNA损伤修复能力的增加却阻碍了疗效的发挥。肿瘤细胞DNA修复能力与化疗敏感性密切相关。近来许多研究表明，DNA修复基因单核苷酸多态性（single nueleotide polymorphism，SNP）、甲基化状态以及基因的过表达均可改变DNA修复的能力，因此检测DNA修复基因的分子状态可以预测个体肿瘤化疗的敏感性。     

ERCC1 基因与非小细胞肺癌关系的研究进展

切除修复交叉互补基因1（ERCCl）是核苷酸切除修复系统的关键基因,切除修复包括铂类药物导致的DNA损伤、紫外线导致的DNA损伤等各种DNA损伤。研究发现其基因表达情况及其多态性与恶性肿瘤的发病、含铂方案的疗效及预后相关,本文着重综述ERCCl与非小细胞肺癌（NSCLC）之间的关系,包括与非小细胞肺癌的发生发展的关系、与铂类药物治疗肺癌疗效及预后的关系。     

非小细胞性肺癌个体化治疗的研究进展

<正>肺癌是全球发病率和病死率最高的肿瘤,其中约80%为非小细胞肺癌(non-small cell lung cancer,NSCLC)。化疗在NSCLC的临床治疗中占有重要地位,但化疗的有效率低、毒副作用大,使得总体疗效并不乐观[1]。近年来,随着基因组学和蛋白质组学的发展,个体化治疗时代已经到来。我们综合分析了与化疗耐药相关的基因及表达情况,为不同类型的NSCLC患者个体化治疗提供参考。一、切除修复交叉互补基因1(ERCC1)ERCC1是核苷酸切除修复系统家族中的标志基因,是一种DNA修复基因,在肺癌细胞的修复过程中对DNA损伤识     

α粒子诱发人支气管上皮细胞癌变的DNA修复基因表达谱研究

背景与目的 :DNA修复系统在细胞基因组完整性维持中发挥重要作用 ,本研究探讨α粒子辐射诱发人支气管上皮细胞癌变的DNA修复基因表达谱变化。 材料与方法 :采用Cy5和Cy3分别标记的癌变细胞BERP35T4和亲本细胞BEP2D的cDNA探针与DNA修复基因cDNA微矩阵杂交、ScanArray3000扫描仪扫描和ImaGene3.0软件分析比较基因表达差异。 结果 :分析比较了人支气管上皮细胞癌变前(BEP2D)和后(BERP35T4)126个DNA修复相关基因的表达谱 ,发现细胞癌变后有10个修复基因的表达降低 ,这些基因分别参与DNA链断裂修复、核苷酸切除修复和碱基切除修复反应 ,3个基因(DNA_PKcs、SMUG和RAD18)表达上调。结论 :细胞DNA修复表达改变是辐射诱发细胞恶性转化的机制之一。     

紫外线诱导皮肤肿瘤形成的分子学机制

肿瘤的发生需要许多遗传学改变,通常认为内源或外源性因素导致DNA损伤后,就会使其在复制过程中出现无限制的自由性的错误修复,从而形成肿瘤.核苷酸切除修复系统在DNA修复过程中最重要,它能有效地识别和清除多种DNA损伤,尤其是紫外线诱导产生的损伤.本文就紫外线对DNA的损伤、DNA损伤后修复途径以及皮肤肿瘤中特殊靶位基因在紫外线相关皮肤肿瘤形成过程中的作用进行了综述.     

XPC基因功能变异与肿瘤发生

着色性干皮病基因组C(XPC)是DNA损伤识别因子,启动DNA修复功能,从而维持细胞的遗传稳定性.DNA修复功能与肿瘤的发生及高异质性有关.现介绍XPC的生物学特性、多态性以及XPC与核苷酸切除修复(NER)、肿瘤发生、细胞周期调节的关系.     

DNA polymerase beta interacts with TRF2 and induces telomere dysfunction in a murine mammary cell line

DNA polymerase beta (Polbeta) is a DNA repair protein that functions in base excision repair and meiosis. The enzyme has deoxyribose phosphate lyase and polymerase activity, but it is error prone because it bears no proofreading activity. Errors in DNA repair can lead to the accumulation of mutations and consequently to tumorigenesis. Polbeta expression has been found to be higher in tumors, and deregulation of its expression has been found to induce chromosomal instability, a hallmark of tumorigenesis, but the underlying mechanisms are unclear. In the present study, we have investigated whether ectopic expression of Polbeta influences the stability of chromosomes in a murine mammary cell line. The results demonstrate a telomere dysfunction phenotype: an increased rate of telomere loss and chromosome fusion, suggesting that ectopic expression of Polbeta leads to telomere dysfunction. In addition, Polbeta interacts with TRF2, a telomeric DNA binding protein. Colocalization of the two proteins occurs at nontelomeric sites and appears to be influenced by the change in the status of the telomeric complex.     

Excision of tamoxifen-DNA adducts by the human nucleotide excision repair system

The antiestrogen tamoxifen is used in the treatment of breast cancer and has recently been recommended as a chemopreventive drug for women at high risk for breast cancer. However, women treated with the drug have an increased incidence of endometrial cancer. It has been suggested that this endometrial cancer might result from mutagenic DNA adducts, which are formed by electrophilic tamoxifen species generated by metabolic activation of the drug. Because the frequency of damage-induced mutations is strongly dependent on the repairability of the lesion, we investigated the repair of the major tamoxifen-DNA adducts by the human nucleotide excision repair system. Using the reconstituted human excision repair system and synthetic DNA substrates, we found that the four types of tamoxifen-DNA adducts detected in the endometrium were repaired with moderate to poor efficiency by nucleotide excision repair. It is concluded that individual variations in repair capacity may play a role in the development of tamoxifen-induced endometrial cancer.     

TRIM44蛋白在肿瘤中的研究进展

TRIM44（tripartite motif-containing 44）是TRIM家族成员,含有B-box、coiledcoil和锌指结构域(RING finger)。TRIM家族作为E3连接酶参与泛素化过程,该酶负责从E2结合酶上转移泛素到特定的靶点上。TRIM蛋白与很多生理学过程有关,包括细胞增殖、DNA修复、信号转导和转录。已有研究证实TRIM蛋白参与肿瘤发生和发展,并且与肿瘤的不良预后有关,TRIM蛋白有望成为肿瘤治疗的新靶点。本文从TRIM44蛋白的基本信息、在肿瘤发生发展中的机制、TRIM44在肿瘤中的研究进展进行阐述。     

Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas

Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)-negative and HPV-positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups. Here, we searched for optimal radiosensitization approaches for HPV-positive and HPV-negative HNSCCs by performing a targeted CRISPR-Cas9 screen. We found that inhibition of base excision repair resulted in a better radiotherapy response in HPV-positive HNSCC, which is correlated with upregulation of genes involved in base excision repair. In contrast, inhibition of nonhomologous end-joining and mismatch repair showed strong effects in both HNSCC groups. We validated the screen results by combining radiotherapy with targeted inhibition of DNA repair in several preclinical models including primary and recurrent patient-derived HNSCC xenografts. These findings underline the importance of stratifying HNSCC patients for combination treatments.     

Variant base excision repair proteins: contributors to genomic instability

Cells sustain endogenous DNA damage at rates greater than 20,000 DNA lesions per cell per day. These damages occur largely as a result of the inherently unstable nature of DNA and the presence of reactive oxygen species within cells. The base excision repair system removes the majority of DNA lesions resulting from endogenous DNA damage. There are several enzymes that function during base excision repair. Importantly, there are over 100 germline single nucleotide polymorphisms in genes that function in base excision repair and that result in non-synonymous amino acid substitutions in the proteins they encode. Somatic variants of these enzymes are also found in human tumors. Variant repair enzymes catalyze aberrant base excision repair. Aberrant base excision repair combined with continuous endogenous DNA damage over time has the potential to lead to a mutator phenotype. Mutations that arise in key growth control genes, imbalances in chromosome number, chromosomal translocations, and loss of heterozygosity can result in the initiation of human cancer or its progression.     

DNA repair and cancer: lessons from mutant mouse models

DNA damage, if the repair process, especially nucleotide excision repair (NER), is compromised or the lesion is repaired by some other error-prone mechanism, causes mutation and ultimately contributes to neoplastic transformation. Impairment of components of the DNA damage response pathway (e.g., p53 ) is also implicated in carcinogenesis. We currently have considerable knowledge of the role of DNA repair genes as tumor suppressors, both clinically and experimentally. The deleterious clinical consequences of inherited defects in DNA repair system are apparent from several human cancer predisposition syndromes (e.g., NER-compromised xeroderma pigmentosum [XP] and p53 -deficient Li-Fraumeni syndrome). However, experimental studies to support the clinical evidence are hampered by the lack of powerful animal models. Here, we review in vivo experimental data suggesting the protective function of DNA repair machinery in chemical carcinogenesis. We specifically focus on the three DNA repair genes, O ⁶-methylguanine-DNA methyltransferase gene ( MGMT ), XP group A gene ( XPA ) and p53 . First, mice overexpressing MGMT display substantial resistance to nitrosamine-induced hepatocarcinogenesis. In addition, a reduction of spontaneous liver tumors and longer survival times were evident. However, there are no known mutations in the human MGMT and therefore no associated cancer syndrome. Secondly, XPA mutant mice are indeed prone to spontaneous and carcinogen-induced tumorigenesis in internal organs (which are not exposed to sunlight). The concomitant loss of p53 resulted in accelerated onset of carcinogenesis. Finally, p53 null mice are predisposed to brain tumors upon transplacental exposure to a carcinogen. Accumulated evidence in these three mutant mouse models firmly supports the notion that the DNA repair system is vital for protection against cancer.     

Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy.

The DNA repair pathways are protective of the host genome in normal cells; however, in cancer cells, these pathways may be disrupted and predispose to tumorigenesis or their activity may overcome the potentially cytotoxic damage caused by anticancer agents and be a mechanism of resistance. Poly(ADP-ribose) polymerase inhibitors, which block base excision repair of single-strand breaks, have entered the clinic in the last few years. This article discusses the interactions between the pathways of single- and double-strand break repair, which explain the two clinical development strategies for this class of drugs.     

Trapping of DNA nucleotide excision repair factors by nonrepairable carcinogen adducts

Nucleotide excision repair is part of a cellular defense system that protects genome integrity.Here, this versatile repair system was challenged with mixtures of DNA adducts that were generated to mimic the wide spectrum of bulky lesions produced by complex genotoxic insults. Probing human excision activity with substrate combinations instead of single lesions resulted in a strong bias for particular base adducts, such that the repair factors were immobilized on a small fraction of damaged DNA, whereas the simultaneous excision of other sites was suppressed. Immobilization of excision factors was also induced by nonrepairable decoy adducts, thereby revealing a mechanism of repair inhibition because of hijacking of critical subunits. Thus, the efficiency of excision repair in response to bulky carcinogen-DNA damage is dependent on an antagonistic interaction with both substrate and decoy adducts.