Spontaneous DNA Damage, Minireview Genome Instability, and Cancer— When DNA Replication Escapes Control
Spontaneous DNA Damage, Minireview Genome Instability, and Cancer— When DNA Replication Escapes Control
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2001
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通讯作者：
Primo Schar
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作者：
Primo Schar
苏黎世大学医学放射生物学研究所和 Paul Scherrer 研究所 CH-8008 苏黎世瑞士 肿瘤的历史增加了染色体稳定性的比率，问题是可能的基因罪魁祸首可能是什么。人类癌症的广泛异质性可以被视为与人类图遗传不稳定性相关的潜在染色体畸变疾病。大多数（如果不是全部）人类肿瘤疾病（Mitelman 等人，1994）表明，多种因素都发挥着某种形式的基因组不稳定性，包括细微不同的细胞过程，因此，大量 DNA 序列改变、总体染色体基因重组可能会受到影响。为简单起见，我们可以分配安排、非整倍性和基因扩增。机械上不同事件的两大类：这些改变有可能影响功能——那些仅影响染色体数量的基因，以及与改变染色体结构的基因相关的生长调节基因。染色体——细胞的恶性转化。因此，为了计算在大多数人类恶性肿瘤中发现的不稳定性的数量——了解肿瘤发展的早期事件，我们需要探索有丝分裂染色体的故障——需要探索一些分离装置（Lengauer等人，1998）通常在人类肿瘤中发现的遗传改变的起源。然而，染色体结构的变化同样是基因组不稳定的基础是不忠实的传递频率，并指出从细胞到其子细胞的遗传信息的DNA代谢传递的不规则性。过程而不是染色体分布。由于这是由于确保这些染色体畸变的细胞功能失效而引起的，因此通常涉及 DNA 处理的准确性，例如 DNA 复制和 DNA 片段的重新连接，因此根本原因、DNA 损伤修复或有丝分裂染色体分布似乎与生成或修复有关。特定的功能缺陷可能与 DNA 链断裂有关。不同模型的研究具有基因组不稳定性的特征模式。已证实，用药物处理细胞，例如，增加保真度的功能失活会导致 DNA 复制的 DNA 双链断裂 (DSB)，或消除诱变 DNA 损伤双国修复，并可能导致染色体重新增强微妙的 DNA 序列改变的速率。排列（Friedberg 等人，1995 年综述）。这可以通过复制后增强有丝分裂重组的表型来说明，这也是元错配修复 (MMR) 或核苷酸切除修复 (NER) 缺陷期间 DNA 链中断的线性积累的结果。 MMR 的故障导致酵母和人类细胞中滞后链 DNA 合成的增加，包括自发突变率、具有缺陷 DNA 连接酶 I 的微卫星 DNA 能力（Lindahland Barnes，1992）以及强烈的、可遗传的癌症倾向。类似地，与 RecQ 样相关的复制缺陷（Jiricny，1998 年综述）。类似地，NER 失败，例如着色性干皮病中的 Sgs1pofyeastorthehomolo-as 等 DNA 螺旋酶和人类细胞的相关遗传性布卢姆螺旋酶 (BLM) 会导致有序性，导致有丝分裂重组和染色体 insta-UV 减少引起的突变率增加，并增加患癌症的风险（在 de Boer bility 中综述（Frei 和 Gasser， 2000）。这些例子支持Hoeijmakers，2000）。这些特定的遗传缺陷的原理是，DNA复制过程中的不规则性在DNA监视中表明，增加可产生重组底物的速率并产生特定形式的基因组不稳定性可导致严重的染色体畸变。肿瘤细胞，从而导致肿瘤的发展。然而，导致更严重的染色体畸变损伤的根本原因通常是在缺乏外部DNA来源的情况下发生的，因此，在人类癌症中占主导地位的染色体不稳定性的增加率较少，因此可以通过任一增加的形式来解释。一个重要的问题是，由于内源性 DNAple 导致的 DNA 链断裂是否适用相同的原理，即代谢缺陷或增强的链间修复不规则的链间定义的遗传缺陷是否可以建立连接，从而改变 DNA 合成或切除过程中出现的染色体断裂率，染色体畸变并加速修复肿瘤的发展？也许迄今为止最有说服力的论据可以定义支持遗传不稳定性假说的DNA链断裂的不规则修复是核，因为当其分配到大多数实体瘤的适当异质性时发生的事件（Mitelman等人修复途径失败。分配到正确的真实al.，1994），这表明新配对系统的持续生成并不像看起来那么微不足道，因为肿瘤进展过程中的遗传变异在选择取决于基因组中的位置以及增加的速率。 Myung 等人的论文。 (2001)在这种生理背景下会发生链断裂；即，一个分期问题
Institute of Medical RadiobiologyUniversity of Zu¨rich and Paul Scherrer InstituteCH-8008 Zu¨richSwitzerlandhistory of a tumor increases the rate of chromosomalinstability, the question arises of what the possible ge-netic culprits might be. The wide heterogeneity of grossHuman cancer can be viewed as a disease of underlyingchromosomal aberrations associated with human tu-genetic instability. Most, if not all human tumors dis-mors (Mitelman et al., 1994) suggests that a variety ofplay some form of genomic instability, including subtledifferent cellular processes and, hence, a great numberDNA sequence alterations, gross chromosomal re-ofgenesmightbeaffected.Forsimplicity,wecanassignarrangements, aneuploidy, and gene amplifications.two major categories of mechanistically distinct events:These alterations have the potential to affect the func- those that simply affect chromosome numbers, andtion of growth-regulating genes that are associated with those that alter chromosome structure. Chromosomethe malignant transformation of cells. Therefore, to un- number instabilities are found in most human malignan-derstand the early events in tumor development, we cies andlikely reflect malfunction ofthe mitotic chromo-need to explore the origin of the genetic alterations that some segregation apparatus (Lengauer et al., 1998).are typically found in human tumors. However, changes in chromosome structure are equallyThe basis of genomic instability is unfaithful transmis- frequent and point to irregularities in DNA metabolic pro-sion of genetic information from a cell to its daughters. cesses rather than in chromosome distribution. SinceThis arises from failure of cellular functions that ensure these chromosomal aberrations usually involve breakagethe accuracy of DNA transactions such as DNA replica- and rejoining of DNA segments, the underlying causetion, DNA damage repair, or mitotic chromosome distri- seems to berelated to either the generationor the repairbution. Specific functional defects can be associated of DNA strand breaks. Studies in different models havewith a characteristic pattern of genomic instability. For established that treatment of cells with agents that in-example, inactivation of functionsthat increase the fidelity duceDNAdouble-strandbreaks(DSB’s)leadstorecom-of DNA replication or eliminate mutagenic DNA lesions binational repair and can give rise to chromosomal re-enhances the rate of subtle DNA sequence alterations. arrangements (reviewed in Friedberg et al., 1995).This is illustrated by the phenotypes of post replicative Enhancedmitoticrecombinationalsoresultsfrommeta-mismatch repair (MMR) or nucleotide excision repair bolic accumulation of DNA strand interruptions during(NER) defects. Malfunction of MMR causes an increase lagging strand DNA synthesis in yeast and human cellsin spontaneous mutation rate, microsatellite DNA insta- with a defectiveDNA ligase I (Lindahland Barnes, 1992).bility, and a strong, heritable predisposition to cancer Similarly, defects in replication associated RecQ-like(reviewed in Jiricny, 1998). Similarly, NER failure, such DNAhelicasessuchastheSgs1pofyeastorthehomolo-as in Xeroderma pigmentosum and related genetic dis- gous Bloom’s helicase (BLM) of human cells cause in-orders, results in increased mutation rates induced by creased mitotic recombination and chromosomal insta-UV and an increased risk of cancer (reviewed in de Boer bility (Frei and Gasser, 2000). These examples supportand Hoeijmakers, 2000). These specific genetic defects the principle that irregularities during DNA replicationin DNA surveillance illustrate that increasing the rate of can generate substrates for recombination and give risea particular form of genomic instability can contribute togrosschromosomalaberrations.Intumorcells,whichto the development of a tumor. However, the underlying usuallyevolveintheabsenceofexternalsourcesofDNAcauses of the more dramatic gross chromosomal aber- damage, an enhanced rate of chromosomal instabilityrations that predominate in human cancers are less could thus be accounted for by either increased forma-clear. An important question is whether the same princi- tion of DNA strand breaks due to an endogenous DNAple applies, i.e., can connections be established be- metabolic defect or enhanced irregular repair of strandtweendefinedgenetic defectsthatalterthe rateofchro- breaks that arise during DNA synthesis or excisionmosomal aberrations and accelerated development of repair.tumors? Perhaps the most convincing argument to date Irregular repair of a DNA strand break can be definedin favor of a genetic instability hypothesis is the karyo- astheeventsthatoccurwhenitsallocationtotheappro-typic heterogeneity of most solid tumors (Mitelman et priate repair pathway fails. Allocation to the proper re-al., 1994), suggesting the persistent generation of novel pair system is not as trivial as it might seem, as thegenetic variants during tumor progression at an in- choice depends on where in the genome and in whichcreased rate. The paper by Myung et al. (2001) in this physiological context strand breaks occur; i.e., a partic-issue of