膀胱癌XPC表达缺失参与影响染色体畸变的分子机制研究
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摘要
一、背景
生物细胞基因组DNA不断受到来自环境的各种外源性因素和来自机体的内源性因素损伤，常见的环境因素包括电离辐射、紫外线、化学毒物等，内源性因子如细胞代谢中间产物及毒素等。面对形式多样的各种DNA损伤，DNA修复就成为维持细胞遗传稳定性和高保真性的一种重要机制。如果DNA修复机制发生改变，将导致损伤的DNA不能被修复或不能被正确修复，从而发生突变，突变的产生将最终导致许多遗传性疾病的发生和肿瘤的形成。
对于不同类型的DNA损伤，机体形成了相应的损伤修复机制。根椐DNA损伤的性质，DNA修复途径大致可以分为：（1）、碱基切除修复；（2）、核苷酸切除修复；（3）、错配修复；（4）、同源重组修复；（5）、非同源末端连接修复和（6）、错误倾向复制。其中，NER途径能够修复多种DNA损伤类型，被认为是维持细胞遗传稳定性的主要途径之一。
DNA修复过程中最关键的环节是对DNA损伤的识别，DNA损伤识别信号将导致细胞对DNA损伤产生上述不同应答效应。XPC分子是NER修复通路中最早的识别蛋白,同时也是NER发挥生物学效应的限速蛋白。XPC基因最初从着色性干皮病C组(Xeroderma Pigmentosum group C)患者中确立,该病是XPC基因缺陷的遗传病。当XPC与HR23B蛋白结合成紧密的复合体XPC/hHR23B,并结合到损伤位点后，进而募集下游一系列分子，完成NER过程。如果XPC表达缺失或功能异常，使损伤的基因组DNA不能被识别修复，将导致DNA突变的发生。
分子流行病学和本课题组前期研究发现，XPC表达沉默是膀胱癌中的高频事件之一。膀胱癌在我国男性泌尿生殖系肿瘤中发病率第一，明显高于西方国家，而且近年来有发病率增加和年轻化趋势。膀胱肿瘤具有高复发、高异质性和耐药的生物学行为，肿瘤细胞遗传学研究普遍显示膀胱癌细胞的染色体存在大量包括不同位点的杂合性缺失、扩增和异倍体等染色体畸变，它是所有人类恶性肿瘤的共同特征，代表着染色体的高遗传不稳定性。我们推测，XPC基因变异或表观遗传学改变，可能直接影响该基因表达或蛋白功能，从而影响DNA修复能力，最终导致高突变的发生，高突变发生是原癌基因和抑癌基因易于突变的基础，也是影响膀胱癌发生和染色体畸变(高异质性)的遗传学基础之一。
染色体畸变是指染色体数目的增减或结构的改变，其结构改变又包括缺失、重复、倒位、易位等。目前对于染色体畸变发生机制的研究多集中在放射等损伤导致的DNA双链断裂研究上。DNA双链断裂（DNA double-strand break，DSB）是对细胞伤害最为严重的一种打击，通常情况下，外源性刺激（电离辐射、γ射线、类辐射药物、拓扑酶抑制剂）及内源性刺激（体内氧化反应产生的自由基）等均会导致这种损伤，一旦损伤不能及时修复，往往会导致染色体的缺失、易位等畸变，从而造成基因组遗传信息的紊乱，最终导致细胞恶变。最近研究发现，XPC不仅作为重要的DNA识别修复蛋白参加NER过程，还可能参与了DNA双链断裂损伤修复（同源重组和/或非同源末端连接修复）的进程，从而影响细胞的命运。
综上所述，我们认为XPC蛋白除了直接参与核酸切除修复外，作为DNA损伤信号还直接或间接参与了如DSB损伤修复等其他DNA修复机制，其功能障碍或缺失将导致基因组DNA突变、缺失或扩增的发生率增加，从而最终影响细胞的命运（生存还是死亡，或者产生高遗传不稳定性细胞）。这也是为什么膀胱癌中XPC低表达，会导致膀胱癌发生、膀胱癌染色体高遗传不稳定性（异质性）的原因。
目前国际上对于DNA修复与肿瘤发生关系的研究，是肿瘤研究领域的一大热点。在分子流行病学和分子病理学的层面发现了极有价值的现象，对其机制的揭示将是未来研究的方向。探索发现DNA修复基因在DDR新的信号功能，对于全新理解肿瘤发生和染色体畸变等高遗传不稳定性的分子机制具有重要的理论意义。
二、目的
1、构建siRNA沉默XPC的稳定细胞株，进行相关细胞功能学实验，为后续进一步研究XPC缺陷影响染色体畸变的分子机制提供细胞模型；
2、在DNA双链损伤剂作用下，观察XPC缺失后是否会导致染色体畸变形成，初步验证我们的推断，为下一步阐明其作用机制奠定基础；
3、探讨XPC缺失后染色体畸变增高是否是由于DSB修复能力降低所致，分析XPC影响DSB修复通路（同源重组修复和非同源末端连接修复）的分子机制，以期最终找到XPC低表达导致膀胱癌染色体高遗传不稳定性的原因。
三、方法
1、siRNA沉默XPC细胞模型的建立及其功能验证：
人工合成XPC干扰序列并将其克隆到能携带siRNA片段的逆转录病毒载体pSilencer5.1-H1-retro上，构建针对人XPC基因特异的RNAi逆转录病毒载体，经测序证实构建成功；瞬时转染HEK293细胞，验证所构建质粒沉默XPC基因表达的效果；通过嘌呤霉素抗性基因，压迫、筛选稳定干扰XPC表达的细胞株；Western blot方法鉴定XPC沉默效果最好的克隆；细胞生长曲线实验观察沉默XPC后，是否影响HEK293细胞的正常生长；以DNA双链损伤剂博来霉素（BLM）和依托泊苷(VP16)处理野生型和XPC低表达细胞，MTT法、克隆形成实验检测其生存曲线及克隆形成率，了解两种细胞对DSB损伤剂的敏感性。
2、XPC表达缺失影响染色体畸变发生的实验研究：
以不同浓度的博来霉素和依托泊苷、采取不同方式处理两种细胞，用细胞质分裂阻滞微核试验(CBMNT)观察微核、核质桥、核芽突等反映染色体畸变和遗传不稳定性的指标；用G显带染色体核型分析方法，研究分析染色体易位、缺失与重复等畸变类型；用SupF突变报告基因系统，研究质粒损伤修复后SupF报告基因的突变频率。从不同的遗传学终点探讨XPC缺失后，染色体畸变的变化情况。
3、XPC表达缺失导致染色体畸变增加的分子机制研究：
DNA双链损伤剂处理后，于损伤修复后不同的时相点收获细胞，利用细胞免疫荧光技术，研究γ-H2AX等双链损伤修复指示分子foci的形成与消除情况；彗星电泳实验，检测细胞DSB损伤后修复能力的变化；Western blot方法研究DNA双链损伤修复通路（同源重组修复和非同源末端连接修复）中关键分子ATM、ATR、Rad51、BRCA2等与XPC表达是否存在关联，揭示XPC表达缺失导致染色体畸变增加可能的分子机制。
四、结果
1、成功构建了siRNA干扰沉默XPC基因表达的稳定细胞株HEK293XPCKD：
构建针对人XPC基因特异的RNAi逆转录病毒载体pSilencer5.1-H1-siXPC-267及其对照质粒pSilencer5.1-H1-N；瞬时转染HEK293细胞，证实其可在HEK293细胞中有效沉默XPC基因表达；稳定转染筛选，Western blot验证发现以clone8（XPCKDcl.8）的XPC沉默效果最好，将其定为HEK293XPCKD细胞，做为后续实验用细胞模型；观察两种细胞生长曲线，发现沉默XPC后不会影响HEK293细胞的正常生长；以DNA双链损伤剂BLM和VP16处理细胞，MTT法及克隆形成实验发现XPC表达缺陷的稳定细胞株HEK293XPCKD，对DNA双链损伤剂更为敏感，其细胞存活率及克隆形成率呈明显下降趋势，提示XPC可能直接或间接地参与了DSBs损伤修复过程。
2、XPC表达缺失导致染色体畸率增高：
以DNA双链损伤剂博来霉素和依托泊苷处理HEK293及HEK293XPCKD细胞，G显带染色体核型分析试验证实XPC缺陷细胞中，染色体易位、缺失、重复等畸变类型增高；CBMNT试验发现，XPC低表达导致在DNA双链损伤时，微核、核质桥、核芽突等反映染色体畸变和遗传不稳定性的指标均大幅度上升；SupF突变报告基因系统提示XPC低表达，会降低细胞对DSB损伤的修复能力，从而导致突变率增加。
3、XPC表达缺失导致的染色体畸变增加是由于DSB损伤修复能力降低引起的：
DNA双链损伤剂处理后，彗星电泳实验发现HEK293XPCKD细胞在损伤修复后不同的时相点，存在更多未被修复的DSB，说明其DSB损伤修复能力降低；细胞免疫荧光技术研究γ-H2AX foci发现，其清除动力学发生改变，XPC缺陷细胞表现为更多的γ-H2AX foci聚集；Western blot实验结果，XPC在DSB损伤发生时可被诱导上调，其表达降低不会影响ATM、ATR等分子的表达，但Rad51、BRCA2随着XPC表达降低也出现下降，提示XPC可能通过影响同源重组修复通路的关键分子表达，使HR修复通路下调，从而影响细胞通过这种高保真方式来修复DSB损伤。
五、结论1.成功构建了siRNA干扰沉默XPC基因表达的稳定细胞株HEK293XPCKD;2.干扰沉默XPC基因表达后，不会影响细胞的正常生长，但会导致XPC表达缺陷细
胞对DNA双链损伤剂更加敏感；3.在DNA双链损伤剂作用下，XPC表达缺陷细胞中染色体易位、缺失、重复等结构
畸变类型增加，微核发生率升高，证实XPC低表达会导致染色体畸变率的增高；4. XPC低表达，可降低细胞对DSB损伤的修复能力和修复速率，使DSB不能被及时
清除，最终导致高突变发生；5. XPC缺陷细胞中核芽突（NBUD）发生率显著升高，同源重组修复通路的关键分子
Rad51、BRCA2随着XPC表达降低也出现下降，提示XPC缺陷时，HR修复通路可
能被下调，从而影响细胞通过这种高保真方式修复DSB损伤；6. XPC缺陷细胞中核质桥（NPB）发生率大幅升高，提示在XPC缺失的情况下，非同
源末端连接（NHEJ）修复通路可能被上调，细胞采取这种有错误倾向的修复方式应
对DSB损伤，可能是其高遗传不稳定性产生的原因。
1. Background
Genomic DNA assaults are abundant due to exogenous environmental factors andcontinuously endogenous ongoing metabolic processes inside the cell, for example, ionizingradiation (IR), ultraviolet (UV) radiation, exposure to chemical agents, metabolic productsand toxinum. Therefore, the DNA repair pathways are of vital importance in maintaininggenomic stability and fidelity. If the mechanism of DNA repair changed, the lesions can resultin persistent DNA damage, eventually lead to carcinogenesis or other genomic diseases.
DNA repair pathways come in many varieties in response to different types of DNAdamage. It can be classified into:(1). base excision repair (BER),(2). nucleotide excisionrepair (NER),(3). Mismatch Repair (MMR),(4). homologous recombination (HR),(5).non-homologous end-joining (NHEJ), and (6). trans-lesion repair. NER pathway is the majorDNA repair pathway that repairs most of the bulky DNA damage generated by UV radiation,chemicals, and chemotherapeutic drugs, making it become one of the most essential repairpathways to keep mammalian cell genomic stability.
The key step of DNA damage repair is the initial damage recognition. XPC is theprimary DNA damage recognition factor and a rate-limiting factor in NER. It is firstidentified in Xeroderma pigmentosum group C patients, those who lack of human XPC gene.After XPC and HR23B combined into XPC/hHR23B complex and binding to the DNAdamaged site，the complex can recruit the consecutive components of NER to finish the repairprocess. It is assumed that XPC deficiency could cause DNA recognition failure, and finallylead to mutations.
Molecular epidemiology study and our previous study show that XPC defects have beenfound in many human solid carcinomas, including bladder cancer. Bladder cancer is the mostcommon tumor of urinary system in the Chinese population, and its incidence is significantly higher than in western country. Bladder tumor is characteristed with high recurrence rate,heterogeneity and drug resistance. Chromosome aberrations are frequently found in bladdercancer cells, such as loss of heterogeneity, amplification and aneuploidy, which is a commonhallmark of human cancer. We assumed that XPC defect may change the capacity of DNArepair, which trigger (pre-)oncogenes and inactivate tumor suppressor genes or otherindispensable genes.
Chromosome aberrations, including chromosome breaks or rearrangements such asdeletion, duplication, inversion and translocation, are reflective of genomic instability. Moststudy about chromosome aberration focused on DNA double-strand breaks caused byradiation. DNA double-strand break is the most severe lesion to genomic DNA. Generally,both exogenous insults (IR,γ-ray, radiomimetic agent and topoisomerase inhibitor) andendogenous insults (free radicals produced by oxidation reaction) can cause this kind ofdamage. If DSBs could not be repaired in time, it will cause genomic instability and inducecell malignant transformation. The accumulated evidences show that XPC may participate inthe repair of DNA double-strand break by HR and/or NHEJ pathway.
To sum up，we assume that the XPC protein might involve in occurrence of chromosomeaberrations via affecting DSBs repair pathway. In current study, we present evidence thatpossible involvement of XPC defect in changing the capacity of DNA double-strand breakrepair resulted in increased chromosome aberrations in bladder cancer.
So far, DNA damage response and carcinogenesis has become a hot issue in tumorresearch field, and valuable phenomenons have been found in molecular epidemiology andmolecular pathology studies. The mechanism should be explored further. Finding novelfunctions of DNA damage repair gene in DDR, will contribute to eventually elucidate themechanism of carcinogenesis and high genomic instability.
2. Objective
(1). Establish XPC-deficient HEK293cell strain by siRNA technology and followed byidentification of cell functions, to develop a cell model for exploring the mechanism betweenXPC deficient and chromosome aberration.
(2). Observe whether XPC silencing could enhance chromosome aberration in responseto DNA double-strand break inducers.
(3). Investigate whether XPC deficient increases chromosome aberration by changing thecapacity of double-strand break repair, and analyse the mechanism of DSB repairpathway choice (HR and/or NHEJ) affected by XPC, eventually find out why XPC defects inbladder cancer could lead to chromosome aberration and genomic instability.
3. Method
(1). Construction and identification of XPC-silenced cell model:
RNAi sequences for XPC is synthesized and cloned into retrovirus vector pSilencer5.1-H1-retro, further identified by DNA sequencing; Transient transfection of HEK293，verification the gene silence effect of the recombinant retrovirus vector; Obtain stableXPC-defect cell strain through the puromycin-resistance gene; Find out the best clone byWestern blot immunoassay; The proliferation ability was investigated by cell growth curve;Treat the wide-type and XPC-defect cells with bleomycin and etoposide, identify thesensitivity of these cells to the DSB agents with MTT assay and clone formation assay.
(2). Study the relationship between XPC deficient and chromosome aberration:
Two types of cells are treated by different concentrations of BLM and VP16in differentways: In the cytokinesis-blocked micronucleus test, the markers which indicated chromosomeaberration and genomic instability, like micronucleus, nucleoplasmic bridge and nuclear buds,are observed; Chromosome aberration, such as translocation, deletion and duplication can bestudied by karyotype analysis with G-banding technique; SupF gene mutation report systemcan be used to investigate mutation rate of SupF after DSB damage.
(3). Investigate whether XPC deficient increases chromosome aberration by changing thecapacity of double-strand break repair:
Harvest wide-type and XPC-defect cells treated with DSB agent in different time pointafter DNA damage, study the formation and elimination ofγ-H2AX foci; Compare theability of DSB repair in different cell lines by comet assay; Using Western blot immunoassay,to find out the relationship between XPC and some key factors in the DNA double-strandbreak repair pathway(HR and NHEJ), such as ATM, ATR, RAD51, BRCA2andγ-H2AX,and then finally reveal the potential molecular mechanism.
4. Results
(1). Stable XPC-defect cell strain HEK293XPCKDwas successfully established:
Construct human XPC specific RNAi vector pSilencer5.1-H1-siXPC-267and controlvector pSilencer5.1-H1-N; Transient transfection of HEK293，the effect of XPC silencinghas been verified; Stable XPC-defect cell strain Clone8（XPCKDcl.8）is identified byWestern blot immunoassay, and named HEK293XPCKDcell as a cell model for thefollowing study; Compared the growth curve of HEK293and HEK293XPCKD cell, XPCsilencing do not affect the normal growth of cell cultures; MTT and clone formation assayshow the XPC deficient cell is much more sensitive to the DSB agents than wide-type withthe treatment of BLM and VP16, indicating that XPC may directly or indirectly involved inthe DSB repair process.
(2). XPC deficient increases chromosome aberration after DSB damage:
HEK293and HEK293XPCKDcell are treated with BLM and VP16at different does.Karyotype analysis with G-banding technique shows that chromosome aberration, such astranslocation, deletion and duplication， significantly increased in XPC deficient cells;CBMNT shows XPC-defect cell exhibit increased frequencies of MNi, NPBs and NBUDswhen compared subjects in the wide-type group; SupF gene mutation report systemdemonstrate that XPC deficient can raise the mutation frequency of SupF gene and decreasethe ability to repair DSBs.
(3). XPC deficient increases chromosome aberration by changing the capacity ofdouble-strand break repair:
Harvest wide-type and XPC-defect cells treated with DSB agent in different time pointafter DNA damage, comet assay and immunofluorescence study demonstrate that XPCdeficient can decrease the ability to repair DSBs; Using Western blot immunoassay, we finddecreased expression of some key factors(Rad51and BRCA2) in the HR repair pathway.Since HR is considered to be an error-free DSB repair pathway, XPC deficient may influencethe ability of HR repair.
5. Conclusions
(1). Stable XPC-defect cell strain HEK293XPCKDwas successfully established;
(2). XPC silencing do not affect the normal growth of cell cultures, but increase thesensitivity of XPC-defect cell to the DSB agents;
(3). In XPC deficient cells, chromosome aberration(such as translocation, deletion andduplication) and frequencies of MNi significantly increased, all these demonstrate that XPCdeficient can raise the rate of chromosome aberration;
(4). XPC deficient can raise the mutation frequency and decrease the ability to repairDSBs;
(5). XPC-defect cell exhibit increased frequencies of NBUDs, and decrease theexpression of some key factors(Rad51and BRCA2) in the HR repair pathway. Since HR isconsidered to be an error-free DSB repair pathway, XPC deficient may influence the ability ofHR repair;
(6). XPC deficiency significantly increased frequencies of NPBs, indicate that NHEJefficiency is up-regulated in the condition of XPC silencing. It could be the reason of highgenomic instability that cell repair DSB damage by this error-prone repair pathway.
生物细胞基因组DNA不断受到来自环境的各种外源性因素和来自机体的内源性因素损伤，常见的环境因素包括电离辐射、紫外线、化学毒物等，内源性因子如细胞代谢中间产物及毒素等。面对形式多样的各种DNA损伤，DNA修复就成为维持细胞遗传稳定性和高保真性的一种重要机制。如果DNA修复机制发生改变，将导致损伤的DNA不能被修复或不能被正确修复，从而发生突变，突变的产生将最终导致许多遗传性疾病的发生和肿瘤的形成。
对于不同类型的DNA损伤，机体形成了相应的损伤修复机制。根椐DNA损伤的性质，DNA修复途径大致可以分为：（1）、碱基切除修复；（2）、核苷酸切除修复；（3）、错配修复；（4）、同源重组修复；（5）、非同源末端连接修复和（6）、错误倾向复制。其中，NER途径能够修复多种DNA损伤类型，被认为是维持细胞遗传稳定性的主要途径之一。
DNA修复过程中最关键的环节是对DNA损伤的识别，DNA损伤识别信号将导致细胞对DNA损伤产生上述不同应答效应。XPC分子是NER修复通路中最早的识别蛋白,同时也是NER发挥生物学效应的限速蛋白。XPC基因最初从着色性干皮病C组(Xeroderma Pigmentosum group C)患者中确立,该病是XPC基因缺陷的遗传病。当XPC与HR23B蛋白结合成紧密的复合体XPC/hHR23B,并结合到损伤位点后，进而募集下游一系列分子，完成NER过程。如果XPC表达缺失或功能异常，使损伤的基因组DNA不能被识别修复，将导致DNA突变的发生。
分子流行病学和本课题组前期研究发现，XPC表达沉默是膀胱癌中的高频事件之一。膀胱癌在我国男性泌尿生殖系肿瘤中发病率第一，明显高于西方国家，而且近年来有发病率增加和年轻化趋势。膀胱肿瘤具有高复发、高异质性和耐药的生物学行为，肿瘤细胞遗传学研究普遍显示膀胱癌细胞的染色体存在大量包括不同位点的杂合性缺失、扩增和异倍体等染色体畸变，它是所有人类恶性肿瘤的共同特征，代表着染色体的高遗传不稳定性。我们推测，XPC基因变异或表观遗传学改变，可能直接影响该基因表达或蛋白功能，从而影响DNA修复能力，最终导致高突变的发生，高突变发生是原癌基因和抑癌基因易于突变的基础，也是影响膀胱癌发生和染色体畸变(高异质性)的遗传学基础之一。
染色体畸变是指染色体数目的增减或结构的改变，其结构改变又包括缺失、重复、倒位、易位等。目前对于染色体畸变发生机制的研究多集中在放射等损伤导致的DNA双链断裂研究上。DNA双链断裂（DNA double-strand break，DSB）是对细胞伤害最为严重的一种打击，通常情况下，外源性刺激（电离辐射、γ射线、类辐射药物、拓扑酶抑制剂）及内源性刺激（体内氧化反应产生的自由基）等均会导致这种损伤，一旦损伤不能及时修复，往往会导致染色体的缺失、易位等畸变，从而造成基因组遗传信息的紊乱，最终导致细胞恶变。最近研究发现，XPC不仅作为重要的DNA识别修复蛋白参加NER过程，还可能参与了DNA双链断裂损伤修复（同源重组和/或非同源末端连接修复）的进程，从而影响细胞的命运。
综上所述，我们认为XPC蛋白除了直接参与核酸切除修复外，作为DNA损伤信号还直接或间接参与了如DSB损伤修复等其他DNA修复机制，其功能障碍或缺失将导致基因组DNA突变、缺失或扩增的发生率增加，从而最终影响细胞的命运（生存还是死亡，或者产生高遗传不稳定性细胞）。这也是为什么膀胱癌中XPC低表达，会导致膀胱癌发生、膀胱癌染色体高遗传不稳定性（异质性）的原因。
目前国际上对于DNA修复与肿瘤发生关系的研究，是肿瘤研究领域的一大热点。在分子流行病学和分子病理学的层面发现了极有价值的现象，对其机制的揭示将是未来研究的方向。探索发现DNA修复基因在DDR新的信号功能，对于全新理解肿瘤发生和染色体畸变等高遗传不稳定性的分子机制具有重要的理论意义。
二、目的
1、构建siRNA沉默XPC的稳定细胞株，进行相关细胞功能学实验，为后续进一步研究XPC缺陷影响染色体畸变的分子机制提供细胞模型；
2、在DNA双链损伤剂作用下，观察XPC缺失后是否会导致染色体畸变形成，初步验证我们的推断，为下一步阐明其作用机制奠定基础；
3、探讨XPC缺失后染色体畸变增高是否是由于DSB修复能力降低所致，分析XPC影响DSB修复通路（同源重组修复和非同源末端连接修复）的分子机制，以期最终找到XPC低表达导致膀胱癌染色体高遗传不稳定性的原因。
三、方法
1、siRNA沉默XPC细胞模型的建立及其功能验证：
人工合成XPC干扰序列并将其克隆到能携带siRNA片段的逆转录病毒载体pSilencer5.1-H1-retro上，构建针对人XPC基因特异的RNAi逆转录病毒载体，经测序证实构建成功；瞬时转染HEK293细胞，验证所构建质粒沉默XPC基因表达的效果；通过嘌呤霉素抗性基因，压迫、筛选稳定干扰XPC表达的细胞株；Western blot方法鉴定XPC沉默效果最好的克隆；细胞生长曲线实验观察沉默XPC后，是否影响HEK293细胞的正常生长；以DNA双链损伤剂博来霉素（BLM）和依托泊苷(VP16)处理野生型和XPC低表达细胞，MTT法、克隆形成实验检测其生存曲线及克隆形成率，了解两种细胞对DSB损伤剂的敏感性。
2、XPC表达缺失影响染色体畸变发生的实验研究：
以不同浓度的博来霉素和依托泊苷、采取不同方式处理两种细胞，用细胞质分裂阻滞微核试验(CBMNT)观察微核、核质桥、核芽突等反映染色体畸变和遗传不稳定性的指标；用G显带染色体核型分析方法，研究分析染色体易位、缺失与重复等畸变类型；用SupF突变报告基因系统，研究质粒损伤修复后SupF报告基因的突变频率。从不同的遗传学终点探讨XPC缺失后，染色体畸变的变化情况。
3、XPC表达缺失导致染色体畸变增加的分子机制研究：
DNA双链损伤剂处理后，于损伤修复后不同的时相点收获细胞，利用细胞免疫荧光技术，研究γ-H2AX等双链损伤修复指示分子foci的形成与消除情况；彗星电泳实验，检测细胞DSB损伤后修复能力的变化；Western blot方法研究DNA双链损伤修复通路（同源重组修复和非同源末端连接修复）中关键分子ATM、ATR、Rad51、BRCA2等与XPC表达是否存在关联，揭示XPC表达缺失导致染色体畸变增加可能的分子机制。
四、结果
1、成功构建了siRNA干扰沉默XPC基因表达的稳定细胞株HEK293XPCKD：
构建针对人XPC基因特异的RNAi逆转录病毒载体pSilencer5.1-H1-siXPC-267及其对照质粒pSilencer5.1-H1-N；瞬时转染HEK293细胞，证实其可在HEK293细胞中有效沉默XPC基因表达；稳定转染筛选，Western blot验证发现以clone8（XPCKDcl.8）的XPC沉默效果最好，将其定为HEK293XPCKD细胞，做为后续实验用细胞模型；观察两种细胞生长曲线，发现沉默XPC后不会影响HEK293细胞的正常生长；以DNA双链损伤剂BLM和VP16处理细胞，MTT法及克隆形成实验发现XPC表达缺陷的稳定细胞株HEK293XPCKD，对DNA双链损伤剂更为敏感，其细胞存活率及克隆形成率呈明显下降趋势，提示XPC可能直接或间接地参与了DSBs损伤修复过程。
2、XPC表达缺失导致染色体畸率增高：
以DNA双链损伤剂博来霉素和依托泊苷处理HEK293及HEK293XPCKD细胞，G显带染色体核型分析试验证实XPC缺陷细胞中，染色体易位、缺失、重复等畸变类型增高；CBMNT试验发现，XPC低表达导致在DNA双链损伤时，微核、核质桥、核芽突等反映染色体畸变和遗传不稳定性的指标均大幅度上升；SupF突变报告基因系统提示XPC低表达，会降低细胞对DSB损伤的修复能力，从而导致突变率增加。
3、XPC表达缺失导致的染色体畸变增加是由于DSB损伤修复能力降低引起的：
DNA双链损伤剂处理后，彗星电泳实验发现HEK293XPCKD细胞在损伤修复后不同的时相点，存在更多未被修复的DSB，说明其DSB损伤修复能力降低；细胞免疫荧光技术研究γ-H2AX foci发现，其清除动力学发生改变，XPC缺陷细胞表现为更多的γ-H2AX foci聚集；Western blot实验结果，XPC在DSB损伤发生时可被诱导上调，其表达降低不会影响ATM、ATR等分子的表达，但Rad51、BRCA2随着XPC表达降低也出现下降，提示XPC可能通过影响同源重组修复通路的关键分子表达，使HR修复通路下调，从而影响细胞通过这种高保真方式来修复DSB损伤。
五、结论1.成功构建了siRNA干扰沉默XPC基因表达的稳定细胞株HEK293XPCKD;2.干扰沉默XPC基因表达后，不会影响细胞的正常生长，但会导致XPC表达缺陷细
胞对DNA双链损伤剂更加敏感；3.在DNA双链损伤剂作用下，XPC表达缺陷细胞中染色体易位、缺失、重复等结构
畸变类型增加，微核发生率升高，证实XPC低表达会导致染色体畸变率的增高；4. XPC低表达，可降低细胞对DSB损伤的修复能力和修复速率，使DSB不能被及时
清除，最终导致高突变发生；5. XPC缺陷细胞中核芽突（NBUD）发生率显著升高，同源重组修复通路的关键分子
Rad51、BRCA2随着XPC表达降低也出现下降，提示XPC缺陷时，HR修复通路可
能被下调，从而影响细胞通过这种高保真方式修复DSB损伤；6. XPC缺陷细胞中核质桥（NPB）发生率大幅升高，提示在XPC缺失的情况下，非同
源末端连接（NHEJ）修复通路可能被上调，细胞采取这种有错误倾向的修复方式应
对DSB损伤，可能是其高遗传不稳定性产生的原因。
1. Background
Genomic DNA assaults are abundant due to exogenous environmental factors andcontinuously endogenous ongoing metabolic processes inside the cell, for example, ionizingradiation (IR), ultraviolet (UV) radiation, exposure to chemical agents, metabolic productsand toxinum. Therefore, the DNA repair pathways are of vital importance in maintaininggenomic stability and fidelity. If the mechanism of DNA repair changed, the lesions can resultin persistent DNA damage, eventually lead to carcinogenesis or other genomic diseases.
DNA repair pathways come in many varieties in response to different types of DNAdamage. It can be classified into:(1). base excision repair (BER),(2). nucleotide excisionrepair (NER),(3). Mismatch Repair (MMR),(4). homologous recombination (HR),(5).non-homologous end-joining (NHEJ), and (6). trans-lesion repair. NER pathway is the majorDNA repair pathway that repairs most of the bulky DNA damage generated by UV radiation,chemicals, and chemotherapeutic drugs, making it become one of the most essential repairpathways to keep mammalian cell genomic stability.
The key step of DNA damage repair is the initial damage recognition. XPC is theprimary DNA damage recognition factor and a rate-limiting factor in NER. It is firstidentified in Xeroderma pigmentosum group C patients, those who lack of human XPC gene.After XPC and HR23B combined into XPC/hHR23B complex and binding to the DNAdamaged site，the complex can recruit the consecutive components of NER to finish the repairprocess. It is assumed that XPC deficiency could cause DNA recognition failure, and finallylead to mutations.
Molecular epidemiology study and our previous study show that XPC defects have beenfound in many human solid carcinomas, including bladder cancer. Bladder cancer is the mostcommon tumor of urinary system in the Chinese population, and its incidence is significantly higher than in western country. Bladder tumor is characteristed with high recurrence rate,heterogeneity and drug resistance. Chromosome aberrations are frequently found in bladdercancer cells, such as loss of heterogeneity, amplification and aneuploidy, which is a commonhallmark of human cancer. We assumed that XPC defect may change the capacity of DNArepair, which trigger (pre-)oncogenes and inactivate tumor suppressor genes or otherindispensable genes.
Chromosome aberrations, including chromosome breaks or rearrangements such asdeletion, duplication, inversion and translocation, are reflective of genomic instability. Moststudy about chromosome aberration focused on DNA double-strand breaks caused byradiation. DNA double-strand break is the most severe lesion to genomic DNA. Generally,both exogenous insults (IR,γ-ray, radiomimetic agent and topoisomerase inhibitor) andendogenous insults (free radicals produced by oxidation reaction) can cause this kind ofdamage. If DSBs could not be repaired in time, it will cause genomic instability and inducecell malignant transformation. The accumulated evidences show that XPC may participate inthe repair of DNA double-strand break by HR and/or NHEJ pathway.
To sum up，we assume that the XPC protein might involve in occurrence of chromosomeaberrations via affecting DSBs repair pathway. In current study, we present evidence thatpossible involvement of XPC defect in changing the capacity of DNA double-strand breakrepair resulted in increased chromosome aberrations in bladder cancer.
So far, DNA damage response and carcinogenesis has become a hot issue in tumorresearch field, and valuable phenomenons have been found in molecular epidemiology andmolecular pathology studies. The mechanism should be explored further. Finding novelfunctions of DNA damage repair gene in DDR, will contribute to eventually elucidate themechanism of carcinogenesis and high genomic instability.
2. Objective
(1). Establish XPC-deficient HEK293cell strain by siRNA technology and followed byidentification of cell functions, to develop a cell model for exploring the mechanism betweenXPC deficient and chromosome aberration.
(2). Observe whether XPC silencing could enhance chromosome aberration in responseto DNA double-strand break inducers.
(3). Investigate whether XPC deficient increases chromosome aberration by changing thecapacity of double-strand break repair, and analyse the mechanism of DSB repairpathway choice (HR and/or NHEJ) affected by XPC, eventually find out why XPC defects inbladder cancer could lead to chromosome aberration and genomic instability.
3. Method
(1). Construction and identification of XPC-silenced cell model:
RNAi sequences for XPC is synthesized and cloned into retrovirus vector pSilencer5.1-H1-retro, further identified by DNA sequencing; Transient transfection of HEK293，verification the gene silence effect of the recombinant retrovirus vector; Obtain stableXPC-defect cell strain through the puromycin-resistance gene; Find out the best clone byWestern blot immunoassay; The proliferation ability was investigated by cell growth curve;Treat the wide-type and XPC-defect cells with bleomycin and etoposide, identify thesensitivity of these cells to the DSB agents with MTT assay and clone formation assay.
(2). Study the relationship between XPC deficient and chromosome aberration:
Two types of cells are treated by different concentrations of BLM and VP16in differentways: In the cytokinesis-blocked micronucleus test, the markers which indicated chromosomeaberration and genomic instability, like micronucleus, nucleoplasmic bridge and nuclear buds,are observed; Chromosome aberration, such as translocation, deletion and duplication can bestudied by karyotype analysis with G-banding technique; SupF gene mutation report systemcan be used to investigate mutation rate of SupF after DSB damage.
(3). Investigate whether XPC deficient increases chromosome aberration by changing thecapacity of double-strand break repair:
Harvest wide-type and XPC-defect cells treated with DSB agent in different time pointafter DNA damage, study the formation and elimination ofγ-H2AX foci; Compare theability of DSB repair in different cell lines by comet assay; Using Western blot immunoassay,to find out the relationship between XPC and some key factors in the DNA double-strandbreak repair pathway(HR and NHEJ), such as ATM, ATR, RAD51, BRCA2andγ-H2AX,and then finally reveal the potential molecular mechanism.
4. Results
(1). Stable XPC-defect cell strain HEK293XPCKDwas successfully established:
Construct human XPC specific RNAi vector pSilencer5.1-H1-siXPC-267and controlvector pSilencer5.1-H1-N; Transient transfection of HEK293，the effect of XPC silencinghas been verified; Stable XPC-defect cell strain Clone8（XPCKDcl.8）is identified byWestern blot immunoassay, and named HEK293XPCKDcell as a cell model for thefollowing study; Compared the growth curve of HEK293and HEK293XPCKD cell, XPCsilencing do not affect the normal growth of cell cultures; MTT and clone formation assayshow the XPC deficient cell is much more sensitive to the DSB agents than wide-type withthe treatment of BLM and VP16, indicating that XPC may directly or indirectly involved inthe DSB repair process.
(2). XPC deficient increases chromosome aberration after DSB damage:
HEK293and HEK293XPCKDcell are treated with BLM and VP16at different does.Karyotype analysis with G-banding technique shows that chromosome aberration, such astranslocation, deletion and duplication， significantly increased in XPC deficient cells;CBMNT shows XPC-defect cell exhibit increased frequencies of MNi, NPBs and NBUDswhen compared subjects in the wide-type group; SupF gene mutation report systemdemonstrate that XPC deficient can raise the mutation frequency of SupF gene and decreasethe ability to repair DSBs.
(3). XPC deficient increases chromosome aberration by changing the capacity ofdouble-strand break repair:
Harvest wide-type and XPC-defect cells treated with DSB agent in different time pointafter DNA damage, comet assay and immunofluorescence study demonstrate that XPCdeficient can decrease the ability to repair DSBs; Using Western blot immunoassay, we finddecreased expression of some key factors(Rad51and BRCA2) in the HR repair pathway.Since HR is considered to be an error-free DSB repair pathway, XPC deficient may influencethe ability of HR repair.
5. Conclusions
(1). Stable XPC-defect cell strain HEK293XPCKDwas successfully established;
(2). XPC silencing do not affect the normal growth of cell cultures, but increase thesensitivity of XPC-defect cell to the DSB agents;
(3). In XPC deficient cells, chromosome aberration(such as translocation, deletion andduplication) and frequencies of MNi significantly increased, all these demonstrate that XPCdeficient can raise the rate of chromosome aberration;
(4). XPC deficient can raise the mutation frequency and decrease the ability to repairDSBs;
(5). XPC-defect cell exhibit increased frequencies of NBUDs, and decrease theexpression of some key factors(Rad51and BRCA2) in the HR repair pathway. Since HR isconsidered to be an error-free DSB repair pathway, XPC deficient may influence the ability ofHR repair;
(6). XPC deficiency significantly increased frequencies of NPBs, indicate that NHEJefficiency is up-regulated in the condition of XPC silencing. It could be the reason of highgenomic instability that cell repair DSB damage by this error-prone repair pathway.
引文
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