Microsatellite instability and expression of DNA mismatch repair genes in malignant astrocytic tumors from adult and pediatric patients

Microsatellite instability (MSI) is used as a molecular marker for defective DNA mismatch repair (MMR) genes.We report here alterations of MSI in 15 malignant astrocytomas (WHO grade Ⅲ) and glioblastomas (GBM; WHO grade Ⅳ) of pediatric patients (2-21 years) and 12 GBM from adults (44-68 years) by comparative analysis of BAT25/BAT26 loci and 10 other microsatellite markers. High-level microsatellite instability (MSI-H) occurred in 4 of the 15 pediatric cases (26.7%) and in 1 of the 12 adult GBM cases (8.3%). Low-level mi-

KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients

AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded.Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used.Expression of MMR proteins including MHL1,MSH2,MSH6 and PMS2 was evaluated by immunohistochemistry.Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age,gender,cancer stage,location,and histology were analyzed.Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.RESULTS:The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%,respectively.KRAS mutations were more common in patients ≥ 50 years old(39.8% vs 22% in patients < 50 years old,P < 0.05).The frequencies of BRAF mutants were higher in tumors from females(6.6% vs males 2.8%,P < 0.05),located in the right colon(9.6% vs 2.1% in the left colon,1.8% in the rectum,P < 0.01),with mucinous differentiation(9.8% vs 2.8% without mucinous differentiation,P < 0.01),or being poorly differentiated(9.5% vs 3.4% well/moderately differentiated,P < 0.05).MMR deficiency was strongly associated with proximal location(20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum,P < 0.001),early cancer stage(15.0% in stages Ⅰ-Ⅱ vs 7.7% in stages Ⅲ-Ⅳ,P < 0.05),and mucinous differentiation(20.2% vs 9.2% without mucin,P < 0.01).A higher frequency of MLH1/PMS2 loss was found in females(9.2% vs 4.4% in males,P < 0.05),and MSH2/MSH6 loss tended to be seen in younger(<50 years old) patients(12.0% vs 4.0% ≥ 50 years old,P < 0.05).MMR deficient tumors were less likely to have KRAS mutations(18.8% vs 41.7% in MMR proficient tumors,P < 0.05) and tumorswith abnormal MLH1/PMS2 tended to harbor BRAF mutations(15.4% vs 4.2% in MMR proficient tumors,P < 0.05).CONCLUSION:The frequency of sporadic CRCs having BRAF mutation,MLH1 deficiency and MSI in Chinese population may be lower than that in the Western population.

Helicobacter pylori infection and expression of DNA mismatch repair proteins

瞄准：为了决定 DNA (MMR ) 蛋白质的表示，包括 hMLH1 和 hMSH2，在在病人与或没有 Helicobacter 的胃的上皮细胞， pylori (H pylori ) 感染了胃炎。方法：五十个 H pylori 积极的病人和 50 H pylori 否定的病人在学习被注册。在有非溃疡消化不良的病人的内视镜检查法期间，二窦和二语料库活体检视为组织学的检查(Giemsa 污点) 并且为免疫被拿 hMLH1 和 hMSH2 的组织化学的染色。结果：为染色的 hMLH1 表明了确实的上皮的房间原子核的百分比是 84.14 +/-7.32% 在 H pylori 否定的病人，当它是 73.34 +/- 时 10.10% 在 H pylori 积极的病人(P 【 0.0001 ) 。没有有效差量关于为染色的 hMSH2 表明了确实的上皮的房间原子核的百分比在二个组之间被看见(81.16 +/-8.32% 在 pylori 否定的 H 对 78.24 +/-8.71% 在 H pylori 积极的病人；P = 0.09 ) 。结论：这研究显示 H pylori 可能通过它影响 DNA MMR 系统的能力部分地至少支持胃的癌的开发。

Association between DNA mismatch repair gene polymorphisms and platinum-based chemotherapy toxicity in non-small cell lung cancer patients

Background:Chemotherapy toxicity is a serious problem from which non-small cell lung cancer(NSCLC) patients suffer.The mismatch repair(MMR) system is associated with platinum-based chemotherapy toxicity in NSCLC patients.In this study,we aimed to investigate the relationship between genetic polymorphisms in the MMR pathway and platinum-based chemotherapy toxicity in NSCLC patients.Methods:A total of 220 Chinese lung cancer patients who received at least two cycles of platinum-based chemotherapy were recruited for this study.Toxicity was evaluated in each patient after two cycles of chemotherapy.A total of 44 single nucleotide polymorphisms were selected to investigate their associations with platinum-based chemotherapy toxicity.Results:MutS homolog 2[MSH2) rs6544991[odds ratio(OR) 2.98,95%confidence interval(CI) 1.20-7.40,P = 0.019]was associated with gastrointestinal toxicity in the dominant model;MSH3 rs6151627(OR 2.38,95%CI 1.23-4.60,P = 0.010),rs6151670(OR 2.05,95%CI 1.07-3.93,P = 0.031),and rs7709909(OR 2.38,95%CI 1.23-4.64,P = 0.010)were associated with hematologic toxicity in the dominant model.Additionally,MSH5 rs805304 was significantly associated with overall toxicity(OR 2.21,95%CI 1.19-4.09,P = 0.012),and M5H5 rs707939 was significantly associated with both overall toxicity(OR 0.42,95%CI 0.23-0.76,P = 0.004) and gastrointestinal toxicity(OR 0.44,95%CI 0.20-0.96,P = 0.038) in the dominant model.Conclusion:Genetic polymorphisms in the MMR pathway are potential clinical markers for predicting chemotherapy toxicity in NSCLC patients.

The Role of DNA Mismatch Repair and Recombination in the Processing of DNA Alkylating Damage in Living Yeast Cells

It is proposed that mismatch repair (MMR) mediates the cytotoxic effects of DNA damaging agents by exerting a futile repair pathway which leads to double strand breaks (DSBs). Previous reports indicate that the sensitivity of cells defective in homologous recombination (HR) to DNA alkylation is reduced by defects in MMR genes. We have assessed the contribution of different MMR genes to the processing of alkylation damage in vivo. We have directly visualized recombination complexes formed upon DNA damage using fluorescent protein (FP) fusions. We find that msh6 mutants are more resistant than wild type cells to MNNG, and that an msh6 mutation rescues the sensitivity of rad52 strains more efficiently than an msh3 mutation. Analysis of RAD52-GFP tagged strains indicate that MNNG increases repair foci formation, and that the inactivation of the MHS2 and MSH6 genes but not the MSH3 gene result in a reduction of the number of foci formed. In addition, in the absence of HR, NHEJ could process the MNNG-induced DSBs as indicated by the formation of NHEJ-GFP tagged foci. These data suggest that processing of the alkylation damage by MMR, mainly by MSH2-MSH6, is required for recruitment of recombination proteins to the damage site for repair.

DNA mismatch repair in trinucleotide repeat instability

Trinucleotide repeat expansions cause over 30 severe neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy type 1, and fragile X syndrome. Although previous studies have substantially advanced the understanding of the disease biology, many key features remain unknown. DNA mismatch repair(MMR) plays a critical role in genome maintenance by removing DNA mismatches generated during DNA replication. However, MMR components,particularly mismatch recognition protein MutSβ and its interacting factors MutLα and MutLγ, have been implicated in trinucleotide repeat instability. In this review, we will discuss the roles of these key MMR proteins in promoting trinucleotide repeat instability.

New functional sites in MutS affect DNA mismatch repair

The MutS protein plays an important role in the DNA mismatch repair system. Mutations in the mutS gene can lead to genome instability and ultimately cell malfunction. Here we have established a method for identifying functional defective mutants of MutS by random mutation and rifampicin screening. Some novel functional sites in MutS were identified. The MutS mutant strains were analyzed using surface plasmon resonance, gel filtration and far-western methods to determine the molecular mechanisms behind the DNA mismatch repair function of MutS.

Preliminary Studies on Base Substitutions and Repair of DNA Mismatch Damage Stimulated by Low Energy N^+ Ion Beam Implantation in Escherichia coli

Ever since the low energy N+ ion beam has been accepted that the mutation effects of ionizing radiation are attributed mainly to direct or indirect damage to DNA. Evidences based on naked DNA irradiation in support of a mutation spectrum appears to be consistent, but direct proof of such results in vivo are limited. Using mutS, dam and/or dcm defective Eschericha coli imitator strains, an preliminary experimental system on induction of in vivo mutation spectra of low energy N+ ion beam has been established in this study. It was observed that the mutation rates of rifampicin resistance induced by N+ implantation were quite high, ranging from 9.2 x 10~8 to 4.9× 10~5 at the dosage of 5.2×1014 ions/cm2. Strains all had more than 90-fold higher mutation rate than its spontaneous mutation rate determined by this method. It reveals that base substitutions involve in induction of mutation of low energy nitrogen ion beam implantation. The mutation rates of mutator strains were nearly 500-fold (GM2929), 400-fold (GM5864) and 6-fold larger than that of AB1157. The GM2929 and GM5864 both lose the ability of repair DNA mismatch damage by virtue of both dam and dcm pathways defective (GM2929) or failing to assemble the repair complex (GM5864) respectively. It may explain the both strains had a similar higher mutation rate than GM124 did. It indicated that DNA cytosine methylase might play an important role in mismatch repair of DNA damage induced by N+ implantation. The further related research were also discussed.

Cost-effective screening using a two-antibody panel for detecting mismatch repair deficiency in sporadic colorectal cancer

BACKGROUND The microsatellite instability(MSI)test and immunohistochemistry(IHC)are widely used to screen DNA mismatch repair(MMR)deficiency in sporadic colorectal cancer(CRC).For IHC,a two-antibody panel of MLH1 and MSH2 or four-antibody panel of MLH1,MSH2,PMS2,and MSH6 are used.In general,MSI is known as a more accurate screening test than IHC.AIM To compare two-and four-antibody panels of IHC in terms of accuracy and cost benefit on the basis of MSI testing for detecting MMR deficiency.METHODS We retrospectively analyzed patients with CRC who underwent curative surgery between 2015 and 2017 at a tertiary referral center.Both IHC with four antibodies and MSI tests were routinely performed.The sensitivity and specificity of a fourand two types of two-antibody panels(PMS2/MSH6 and MLH1/MSH2)were compared on the basis of MSI testing for detecting MMR deficiency.RESULTS High-frequency MSI was found in 5.5%(n=193)of the patients(n=3486).The sensitivities of the four-and two types of two-antibody panels were 97.4%,92.2%,and 87.6%,respectively.The specificities of the three types of panels did not differ significantly(99.6%for the four-antibody and PMS2/MSH6 panels,99.7%for the MLH1/MSH2 panel).Based on Cohen's kappa statistic(κ),four-and twoantibody panels were in almost perfect agreement with the MSI test(κ>0.9).The costs of the MSI test and the four-and two-antibody panels of IHC were approximately$200,$160,and$80,respectively.CONCLUSION Considering the cost of the four-antibody panel IHC compared to that of the twoantibody panel IHC,a two-antibody panel of PMS2/MSH6 might be the best choice in terms of balancing cost-effectiveness and accuracy.

A brief history of the DNA repair field

损坏脱氧核糖核酸的修理的历史能被跟踪到 mid-1930s。从那以后多重的脱氧核糖核酸修理机制，以及对脱氧核糖核酸的另外的生物回答损坏，被发现了，他们的规定被学习了。这篇文章简短描述这个领域的早历史。

Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer

AIM: To shed light on the possible role of mismatch repair gene Mlh3 in familial esophageal cancer (FEC). METHODS: A total of 66 members from 10 families suggestive of a genetic predisposition to hereditary esophageal cancer were screened for germline muta-tions in Mlh3 with denaturing high performance liquid chromatography (DHPLC), a newly developed method of comparative sequencing based on heteroduplex detec-tion. For all samples exhibiting abnormal DHPLC profi les, sequence changes were evaluated by cycle sequencing. For any mutation in family members, we conducted a segregation study to compare its prevalence in sporadic esophageal cancer patients and normal controls. RESULTS: Exons of Mlh3 in all samples were successful-ly examined. Overall, 4 missense mutations and 3 poly-morphisms were identifi ed in 4 families. Mlh3 missense mutations in families 9 and 10 might be pathogenic, but had a reduced penetrance. While in families 1 and 7, there was no suffi cient evidence supporting the mono-genic explanations of esophageal cancers in families. The mutations were found in 33% of high-risk families and 50% of low-risk families. CONCLUSION: Mlh3 is a high risk gene with a reduced penetrance in some families. However, it acts as a low risk gene for esophageal cancer in most families. Muta-tions of Mlh3 may work together with other genes in anaccumulated manner and result in an increased risk ofesophageal tumor. DHPLC is a robust and sensitive tech-nique for screening gene mutations.

子宫内膜癌组织中dMMR蛋白和miRNA Let-7表达水平及临床价值的研究

目的探讨子宫内膜癌(endometrial carcinoma,EC)中微小RNA Let-7(miRNA Let-7)表达水平与DNA错配修复(DNA mismatch repair,dMMR)蛋白表达缺失的关系及意义。方法选取2016年5月~2022年12月在江苏省连云港市妇幼保健院行根治性手术切除的子宫内膜癌患者74例,分别用免疫组织化学法检测dMMR蛋白(包括MLH1,PMS2,MSH2,MSH6)的表达、实时荧光定量聚合酶链反应(qRT-PCR)检测miRNA Let-7的相对表达量,按照dMMR蛋白表达情况,将EC患者分为表达完整组(n=43)和表达缺失组(n=31),采用Logistic多因素回归分析与dMMR蛋白缺失相关的危险因素、绘制受试者工作特征(receiver operating characteristic,ROC)曲线评估相关因素的预测价值。结果74例EC病例中,miRNA Let-7的表达水平在肌层浸润<1/2组显著高于肌层浸润≥1/2组,差异具有统计学意义(t=1.79,P=0.04);dMMR蛋白表达的缺失率为41.89%,且年龄<55岁组和miRNA Let-7低表达组(<0.715)患者中的dMMR蛋白缺失率高于≥55岁组和miRNA Let-7高表达组(≥0.715),差异具有统计学意义(χ2=3.92,4.50,均P<0.05);Logistic多因素回归分析结果显示miRNA Let-7表达水平是发生dMMR表达缺失的独立危险因素(P=0.012);Spearman相关分析表明,miRNA Let-7的表达水平与dMMR蛋白缺失呈明显负相关(r=-0.247,P=0.034);ROC曲线分析结果显示,miRNA Let-7表达水平对于预测EC患者中发生dMMR蛋白的缺失具有一定的价值,其AUC为0.737,最佳临界值为0.77,敏感度和特异度分别为0.651,0.806。结论子宫内膜癌患者中miRNA Let-7的表达水平与dMMR蛋白缺失具有相关性,也是发生dMMR蛋白缺失的危险因素,有望为预测dMMR的表达缺失提供帮助。

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

DNA错配修复基因甲基化在H446细胞获得性耐药中的作用

目的探讨DNA错配修复基因MLH1(human MutL homolog1)、MSH2(human MutS homolog2)甲基化在人小细胞肺癌H446细胞获得性耐药中的作用。方法RT-PCR及Western blot法检测H446细胞及其多药耐药细胞H446/DDP中MLH1、MSH2基因的mRNA表达和蛋白表达,甲基化特异性PCR(MSP)法检测MLH1、MSH2基因启动子CpG岛甲基化状态。结果H446/DDP细胞中MLH1、MSH2基因的mRNA及蛋白水平均较H446细胞显著降低(P<0.01),且其启动子甲基化程度明显增强。结论DNA错配修复基因MLH1、MSH2启动子甲基化诱导其表达下调可能是人小细胞肺癌获得性耐药的重要机制之一。

DNA错配修复与癌症的发生及治疗

DNA错配修复是细胞复制后的一种修复机制,具有维持DNA复制保真度,控制基因变异的作用。DNA错配修复缺陷使整个基因组不稳定,最终会导致肿瘤和癌症的发生。DNA错配修复系统不仅通过矫正在DNA重组和复制过程中产生的碱基错配而保持基因组的稳定,而且通过诱导DNA损伤细胞的凋亡而消除由突变细胞生长形成的癌变。错配修复缺陷细胞的抗药性也引起了癌症化疗研究方面的关注。大多数情况下,错配修复健全型细胞对肿瘤化疗药物敏感,而错配修复缺陷细胞却有较高的抗性。DNA错配修复系统通过修复和诱导细胞凋亡维护基因组稳定的功能,显示了错配修复途径在癌症生物学和分子医学中的重要性。

DNA错配修复蛋白缺失与Ⅱ、Ⅲ期结肠癌根治术后复发转移及预后的关系

目的探讨DNA错配修复蛋白(MMR)缺失与Ⅱ、Ⅲ期结肠癌根治术后复发转移及预后的关系。方法采用免疫组织化学法检测294例结肠癌患者手术标本的MMR表达,回顾性分析其表达对结肠癌患者临床病理参数及生存率的影响。结果多因素分析结果显示,肿瘤部位、分化程度和分期是影响MMR表达状态的独立性危险因素(P<0.05);单因素结果显示,年龄、分化程度、T和N分期是影响患者复发转移率、总体生存率的危险因素;仅有N分期是影响患者复发转移率的独立性危险因素;仅有肿瘤分化程度、N分期和MMR缺失是影响患者总体生存率的独立性危险因素。220例DNA错配修复缺陷蛋白完整(pMMR)患者中,69例出现复发转移(31.4%),48例死亡(21.8%);74例DNA错配修复蛋白缺失(dMMR)患者中,13例出现复发转移(17.6%),9例死亡(12.2%)。两组患者的无病生存率(P=0.034)、总体生存率(P=0.047)差异均具有统计学意义。结论肿瘤部位、分化程度和分期与MMR表达状态密切相关;MMR表达缺失患者预后明显较差,可作为判断患者预后的一个潜在标志物。

DNA错配修复蛋白表达与胃腺癌临床病理特征的关系及意义

目的:检测DNA错配修复(mismatch repair,MMR)主要蛋白(MLH1、MSH2、MSH6和PMS2)在人胃腺癌组织中的表达,并分析错配修复缺陷(defective mismatch repair,dMMR)与胃腺癌临床病理因素及预后的关系。方法:采用免疫组织化学染色法检测4种MMR蛋白(MLH1、MSH2、MSH6和PMS2)在120例人胃腺癌组织中的表达,并从癌症基因组图谱(The Cancer Genome Atlas,TCGA)公共数据库下载432例胃腺癌患者的临床病理资料和微卫星不稳定性(microsatellite instability,MSI)的检测结果,分析MSI与胃腺癌临床病理特征的关系,利用TCGA的数据分析高频度微卫星不稳定(MSI-H)与胃腺癌患者预后的关系。结果:免疫组化染色结果显示在120例胃腺癌组织中,MMR蛋白表达正常(pMMR)组106例(88.3%),MMR蛋白表达缺失(dMMR)组14例(11.7%),其中MLH1缺失2例(1.7%)、PMS2缺失13例(10.8%)、MLH1和PMS2共同缺失2例(1.7%)、MSH2和MSH6共同缺失1例(0.8%)。统计分析结果显示,dMMR与胃腺癌淋巴结转移相关( P =0.022),而与其他临床病理因素无关。TCGA数据统计分析结果显示,MSI-H与胃腺癌患者年龄( P =0.001)、性别( P =0.000)、原发肿瘤部位( P =0.000)、Lauren分型( P =0.011)、肿瘤浸润深度T分期( P =0.024)、淋巴结有无转移( P =0.008)有关。Kaplan-Meier生存分析结果显示MSI-H型胃腺癌患者有预后更好的趋势,但差异不具有统计学意义( P =0.070)。结论:120例中国胃腺癌患者中MSI/dMMR型胃腺癌占比为11.7%,且dMMR状态与胃腺癌的淋巴结转移呈负相关;MSI-H型胃腺癌患者具有年龄大、多为女性、肿瘤多位于胃远端、肿瘤浸润深度T分期低、无淋巴结转移的特征,且MSI-H型胃腺癌具有预后更好的趋势,但不具有统计学意义。MSI状态与胃癌预后的关系尚需进一步深入研究和大样本数据的验证。

结直肠癌DNA错配修复蛋白的表达及临床病理学意义

目的探讨错配修复蛋白在结直肠癌中的表达及临床病理学意义。方法采用免疫组织化学法,对55例结直肠癌组织标本进行MLH1、MSH2、MSH6、PMS2四种错配修复蛋白检测,同时观察其与临床病理学参数关系。采用real-time PCR法对其中10例进行鼠类肉瘤病毒癌基因(KRAS)第2号外显子和鼠类肉瘤滤过性毒菌致癌基因同源体B1(BRAF)基因第15号外显子突变检测。结果 55例患者中50例四种蛋白均阳性表达,为微卫星稳定(MSS),5例患者蛋白表达有缺失,提示为高频微卫星不稳定(MSI-H),缺失率为9.09%,其中4例MLH1、PMS2联合缺失,1例MSH2、MSH6联合缺失;MSI-H患者肿瘤多发生在右半结肠,与MSS患者相比差异显著(P=0.01),其中3例为黏液癌或伴黏液分化癌,均无淋巴结转移;10例行KRAS及BRAF突变检测的病例中,6例存在KRAS基因突变,1例存在BRAF基因突变且表现为MLH1、PMS2表达联合缺失。结论 MSI-H结直肠癌患者多发生在右半结肠,这类患者有以黏液癌或伴有黏液分化癌多见及淋巴结转移少见为特征的趋势;MSI-H与MSS患者相比,在年龄、性别、肿块大小、肿瘤分级及分期方面无显著差异;发现散发性结直肠癌中具有微卫星不稳定的病例,结合其他检测可进一步指导临床用药,为新的治疗方案提供理论依据。

DNA错配修复系统组成和功能的研究进展

DNA错配修复(Mismateh repair,MMR)系统广泛的存在于从原核到真核的生物体中,是进化上保守的生化通路。MMR系统由一系列特异性修复DNA碱基错配的酶分子(错配修复基因产物)组成。细胞由于此系统的存在使DNA复制保持忠实性,从而保持遗传物质的完整性和稳定性,避免遗传物质发生突变。MMR系统基因的失活会导致自发突变率的明显增加,从而导致微卫星不稳定(MSI),可能引发某些肿瘤发生。近年来,MMR系统的研究越来越受到学者的重视,对MMR作用机制及组成该系统的几种酶蛋白结构与功能方面的研究不断深入,加深了对MMR系统的理解。这些为MMR系统相关的应用研究,尤其是为肿瘤发生奠定了理论的基础。本文重点讨论了错配修复系统的蛋白组成、各蛋白的功能及它们如何相互协调发挥作用的最新研究进展。

DNA错配修复基因hMLH1与肿瘤及化疗耐药相关性的研究进展

DNA是生命活动最重要的遗传物质。DNA复制产生的误差(碱基错配)是一种重要的损伤。若DNA损伤得不到修复,将会导致基因的突变,其中一部分突变有利于物种的进化,而另一部分将导致细胞恶化和死亡。DNA错配修复系统(mismatch repair system,MMR)是人体细胞中存在的一种能识别并修复DNA碱基错配的安全保障系统。到目前为止,已从人体细胞中共分离克隆到9种MMR基因。hMLH1基因是一系列DNA错配修复基因中最重要的一种,也是MMR系统的重要成分,其甲基化可导致MMR缺陷。近年来的研究发现,hMLH1的失活与肿瘤发生发展有关,并可能因此导致肿瘤对某些抗肿瘤药物耐药。