DNA的损伤与修复


 DNA的损伤与修复机制

突变的形成和癌症的发展均涉及细胞DNA的损伤。人体细胞中的DNA每天都会遭受数千次到百万次由外部(外源)和内部代谢(内源)带来的破坏。在DNA的转录和随后转译成信号传导和细胞功能必需的蛋白质的过程中,细胞基因组的改变可能会导致错误的产生。如果基因组突变未能在有丝分裂前得到修复,则该突变也可能会携带到子细胞中。一旦细胞无法有效修复受损的DNA,将会产生三种可能的应答(见图1)

  1. 细胞可能会衰老,即进入不可逆的休眠状态。2005年,多个实验室研究发现,在体内和体外实验中,癌细胞均可发生衰老现象,停止有丝分裂并阻止细胞的进一步进化。1-4
  2. 细胞可能会凋亡。足量的DNA损伤会启动一个凋亡信号级联反应,强迫细胞进入细胞死亡程序。
  3. 细胞会恶变,即具有永生特性并开始不受控制的分裂。

引起衰老、凋亡和癌变的细胞DNA损伤与修复的途径

图1. 引起衰老、凋亡和癌变的细胞DNA损伤与修复的途径

为了弥补已发生的不同程度不同类型的DNA损伤,细胞会进行多种不同修复程序,包括错配、碱基切除和核苷酸切除修复机制,各机制之间基本不会出现冗余处理。如果发生了过度损伤,无法通过消耗能量来有效修复的话,细胞会进入到衰老或凋亡过程。细胞能有效修复损伤的几率取决于细胞的种类和年龄。


 DNA损伤的来源

多年来,外源损伤一直被认为是引起致癌DNA突变的主要因素。但是,Jackson和Loeb认为,内源导致的DNA损伤也极大有助于引起致癌突变。5 来自环境和细胞的诱因可以造成相似的DNA损伤。

DNA可以被物理的和化学的诱变剂攻击。物理诱变剂主要是各种辐射源,包括来自太阳的UV(200-300 nm波长)辐射。UV辐射可以在DNA链的相邻嘧啶(胞嘧啶和胸腺嘧啶)的碱基之间形成共价键从而产生交联。电离辐射(X光)在细胞内生成自由基,从而产生活性氧(ROX),造成双螺旋结构中单链和双链断裂,引发DNA突变。化学诱变剂可以将烷基共价连接到DNA碱基上;氮芥化合物可以甲基化或乙基化DNA碱基,是一种DNA烷化剂。前致癌物是化学惰性的前体物质,可以通过代谢转化为高活性的致癌物质。这些致癌物质可以与DNA反应,形成DNA加合物,即一种连接到DNA上的化学实体。苯并[a]芘是一种多环芳烃,本身并不致癌, 在细胞色素P450酶作用下,经过两个连续的氧化反应,生成环氧苯并[a]芘(BPDE),后者是一种致癌代谢物,可以形成共价DNA加合物(见图2)。

苯并[a]芘被P450酶氧化生成高致癌的环氧苯并[a]芘

图2. 苯并[a]芘被P450酶氧化生成高致癌的环氧苯并[a]芘。

DNA 损伤也可能是由内源代谢或生化反应导致,其中一些过程还未被充分了解。6 水解反应可以将核苷酸碱基从DNA链上部分或全部切割下来。连接嘌呤碱基(腺嘌呤或鸟嘌呤)和脱氧核糖磷酸链的化学键在被称为脱嘌呤的过程会自发断裂。在哺乳动物细胞中,每天估计会发生10,000次脱嘌呤事件。7 而脱嘧啶(从胸腺嘧啶或胞嘧啶中失去嘧啶碱基)的发生概率会比脱嘌呤低20-100倍。

脱氨基作用是指在细胞内,腺嘌呤、鸟嘌呤和胞嘧啶环失去氨基,分别变成次黄嘌呤、黄嘌呤和尿嘧啶。DNA修复酶能够识别并修正这些异常碱基。但是,未被修正的尿嘧啶在之后的DNA复制过程中可能会被误读为胸腺嘧啶从而产生C→T点突变。

DNA甲基化是由细胞内的S-腺苷甲硫氨酸(SAM)反应引起的一种特殊形式的烷基化。SAM是一种细胞内代谢中间体,含有高活性的甲基基团。在哺乳动物的细胞中,甲基化发生在胞苷碱基(C)的胞嘧啶环的5号位置上,对应鸟嘌呤碱基(G)的5’,即序列CpG。甲基化产物5-甲基胞嘧啶的自发的脱氨基作用是突变错误的一个主要来源。氨基的丢失会产生一个胸腺嘧啶碱基,后者不会被DNA修复酶认定为异常碱基, 从而使得这一置换在DNA复制中被保留,形成C→T点突变(见图3)。

胞嘧啶的二段突变产生了胸腺嘧啶,形成了C→T点突变。

图3. 胞嘧啶的二段突变产生了胸腺嘧啶,形成了C→T点突变。

正常的代谢过程会产生活性氧(ROS),后者会通过氧化反应修饰碱基。嘌呤和嘧啶类碱基均会被氧化。最常见的突变是鸟嘌呤被氧化成8-氧代-7,8-二氢鸟嘌呤,从而形成核苷酸8-氧代-脱氧鸟苷(8-oxo-dG)。8-oxo-dG可以与脱氧腺苷碱基配对,而不是预期的脱氧胞苷。如果这一错误未被错配修复酶发现并修正,则之后复制的DNA将会包含C→A点突变。ROS也可能会引起DNA脱嘌呤、脱嘧啶以及单链或双链的断裂。

在细胞周期的S期进行的DNA复制可能会引入其他类型的基因突变。复制DNA模板的聚合酶有很小的但不可忽视的错误率,对比模板DNA,会将错误的核苷酸按Watson-Crick配对原则整合进合成链中。发生化学改变的核苷酸前体也可能被聚合酶整合进合成的DNA中,取代正常的碱基。此外,在复制含有大量的重复氨基酸或者重复序列(微卫星区域)的DNA片段时,聚合酶容易发生“打滑”现象。当模板DNA链和复制的DNA链滑脱正确的排列时,链的滑动会导致出现这一酶学上的“打滑”现象。后果是聚合酶无法正确插入模板DNA指定数量的核苷酸,导致子链核苷酸过多或过少。

DNA的单链和双链可能会发生断裂。单链的断裂可能是由于DNA脱氧核糖磷酸链上的脱氧核糖部分的损伤引起的。在AP-核酸内切酶1去除脱氧核糖磷酸基团后进行的碱基切除修复路径的中间步骤也可能发生断裂。8 当单链断裂发生时,核苷酸碱基和脱氧核糖骨架都会从DNA结构上丢失。双链断裂最常发生在细胞传代的S期中,此时DNA解开螺旋以作为复制模板,从而更容易断裂。


 DNA修复机制

细胞可以进化到凋亡或衰老状态,这可以看成是细胞最终的手段。对于不同的DNA损伤,细胞会进化出特定的方法修复损伤或清除损伤化合物。

O6-甲基鸟嘌呤DNA甲基转移酶(MGMT;DNA烷基转移酶)从DNA结构的鸟嘌呤碱基上切除甲基和乙基加合物。这一反应并不是催化(酶促)反应,而是化学计量(化学)反应,每去除一个加合物,就消耗一个分子的MGMT。经过改造的MGMT过表达的细胞对于癌症的耐受性更强,这可能是因为它们可以抵消更多的烷基损伤。Niture等人最近的一项研究表明,使用半胱氨酸/谷胱甘肽加强的药物和天然抗氧化剂,可以提高MGMT的表达。9

具有校正活性的DNA聚合酶,例如聚合酶-δ,主要参与复制错误的修复。当错误被检出时,这些聚合酶会停止DNA复制过程,退回去消除子链DNA上的核苷酸,直至错误核苷酸被消除,然后再重新开始正向的复制过程。研究数据显示,相对于野生型或单拷贝突变的小鼠来说,在Pold1基因双拷贝过程中均发生点突变的小鼠表现出DNA聚合酶-δ校正活性的损失,并且上皮性肿瘤的发病率明显上升。10

被称为错配切除修复(MMR)酶的一组蛋白质可以修正复制过程中DNA聚合酶的校正活性未检出的错误。MMR酶可以切除子链DNA上的错误核苷酸,并以母链DNA作为正确的模板,通过W-C配对修复链。11 这一点对于微卫星区域复制中产生的错误尤其重要,因为DNA聚合酶的校对活性无法检测出这些错误。在有限程度内,MMR酶可以修正由DNA氧化或烷化导致的多种碱基配对异常。这些突变包括含有O6-甲基鸟嘌呤和8-氧鸟嘌呤的修饰碱基对、致癌物质和顺铂加合物。12,13 人类错配切除修复基因MSH2和MLH1的突变与遗传性非息肉性结直肠癌(HNPCC)综合症有关。14


 碱基切除修复和核苷酸切除修复

碱基切除修复(BER)过程包含多种酶来对单一受损的核苷酸碱基进行切除和替换。BER酶主要修复由内源氧化作用和水解作用导致的碱基修饰。DNA糖基化酶切割核苷酸碱基和核糖间的化学键,得到完整的DNA核糖磷酸链,但是会产生无嘌呤或无嘧啶(AP)的位点。8-氧鸟嘌呤DNA糖基化酶(Ogg1)可以除去7,8-二氢-8-氧鸟嘌呤(8-oxoG),后者是一种由活性氧引起的碱基突变。人OGG1基因的多态性与多种癌症如肺癌和前列腺癌的风险相关。尿嘧啶DNA糖基化酶是另一种BER酶,可以切除胞嘧啶脱氨基产生的尿嘧啶,从而防止随后的C→T点突变。15 N-甲基嘌呤DNA糖基化酶(MPG)可以去除大量被修饰的嘌呤碱基。16

由BER酶反应产生的以及由脱嘧啶和脱嘌呤作用产生的DNA中的AP位点,可以被AP-核酸内切酶1(APE1)修复。APE1可以切割AP位点磷酸二酯链的5’位置, 使得DNA链产生3’-羟基基团和5’-碱基脱氧核糖磷酸基团。DNA聚合酶β(Polβ)基于相应的W-C配对插入正确的核苷酸,并通过相关的AP裂解酶活性去除脱氧核糖磷酸基团。X射线修复交叉互补组1(XRCC1)的存在对于DNA连接酶III(LIG3)形成异二聚体是必须的。XRCC1充当支架蛋白,为Polβ提供一个非活性结合位点,并将Polβ和LIG3酶一同带至修复位点。17 聚(ADP-核糖)聚合酶(PARP-1)与XRCC1和Polβ相互作用,是BER途径的必要组成部分。18,19 修复的最后一步是由LIG3完成的,它将用来替代核苷酸的脱氧核糖与脱氧核糖磷酸骨架连接起来。这一修复途径被称作“短补丁BER”。20

另一条被称作“长补丁BER”的修复路径可以置换最小长度为2个核苷酸的核苷酸链。据报道,该途径可以修复10到12个核苷酸长度的核苷酸链。21,22 长补丁BER需要增殖细胞核抗原(PCNA)作为重建酶的支架蛋白。23 其他的DNA聚合酶,可能为Polδ和Polε,24 用于生成寡核苷酸瓣状侧翼。已有的核苷酸序列被瓣状核酸内切酶-1(FEN1)去除, 随后寡核苷酸通过DNA连接酶 1(LIG1)连接至DNA上,填补缺口并完成修复。17 有关短补丁BER和长补丁BER途径选择的机制仍然在研究中(见图4)。25

短补丁和长补丁途径的原理图

 

图 4. 短补丁和长补丁途径的原理图。

尽管BER可以通过长补丁途径置换多个核苷酸,但短补丁和长补丁BER都是由单个核苷酸的损伤引起的,从而将对DNA双螺旋结构的影响降至最低。核苷酸切除修复(NER)可以修复产生了DNA结构扭曲的核苷酸链(含至少2个碱基)的损伤。除了修复由较大的DNA加合物和UV射线的外源因素造成的连续性损伤外,NER还可以修复单链断裂。26 该途径还可以用于修复氧化应激造成的损伤27 在哺乳动物细胞中,有超过20种蛋白质参与了NER途径,包括XPA、XPC-hHR23B、复制蛋白A(RPA)、转录因子TFIIH、XPB和XPD DNA解旋酶、ERCC1-XPF和XPG、Polδ、Polε、PCNA和复制因子C。28 切除修复交叉互补(ERCC1)基因的过度表达与非小细胞的肺癌细胞的顺铂耐受性有关,29 并可以增强DNA修复能力。30 全基因组NER(GGR)可以修复整个基因组内的损伤,而被称作转录偶联修复(TCR)的特殊的NER途径可以在活性RNA聚合酶转录过程中修复基因。31 


 双链断裂修复

DNA的双链断裂可以导致基因序列的丢失和重排。这些断裂可以通过非同源末端连接(NHEJ)或者同源重组(HR)来修复,也被称作重组修复或模板辅助修复。

当细胞处于S/G2阶段后期且模板近期被复制时,HR途径被激活。这一机制需要一个通过着丝粒与DNA受损区域连接的相同或近乎相同的序列作为修复模板。通过该机制修复的双链断裂通常是因为复制机试图跨过单链的断裂位置或未修复的损伤进行合成,导致了复制叉结构的崩溃而引起的。

在细胞循环的其他节点,当姐妹染色体不能作为HR模板时,会启动非同源末端连接(NHEJ)途径。当断裂发生时,细胞不会复制包含断裂部位的DNA区域,因此与HR途径不同,没有相应的模板链可用。在NHEJ途径中,Ku异二聚体蛋白位于断裂的DNA链的两端,在没有模板可用的情况下进行修复,因此在该过程中可能会丢失序列信息。有多种酶参与了重连过程,包括DNA连接酶IV,XRCC4和DNA依赖性蛋白激酶(DNA-PK)。32,33 NHEJ具有内在的致突变性,因为它依赖于两条需要连接的DNA片段的单链尾端的机会配对,称为微同源性(见图5)。在高级真核细胞中,DNA-PK对NHEJ修复是必需的,无论是主要机制还是替代性的备用机制(D-NHEJ)。34

NHEJ修复DNA双链断裂的常规机制。

图5. NHEJ修复DNA双链断裂的常规机制。


 DNA的损伤与修复未来的应用

虽然DNA损伤是癌细胞发展和进化的关键因素,连续性的损伤仍然被用作癌症临床治疗的一部分,用于迫使恶性细胞进入凋亡或衰老状态。很多化学治疗药物是有效的,例如博来霉素、丝裂霉素和顺铂,因为它们会对复制速率比周围组织快的癌细胞造成进一步的DNA损伤。细胞DNA修复机制是一把双刃剑,一方面它可以减少致癌突变,从而保证基因组的完整性,但是另一方面,在恶性细胞中,同样的机制又会使得细胞免于更多的DNA损伤并持续不可控增长。为了阻断癌细胞内的这一存活机制,临床试验中现在开始使用特定DNA修复酶(包括MGMT、PARP和DNA-PK)的抑制剂。35-38 


 DNA的损伤与修复的材料

     


 DNA的损伤与修复的参考文献

Manuel Collado, Jesús Gil, Alejo Efeyan, Carmen Guerra, Alberto J Schuhmacher, Marta Barradas, Alberto Benguría, Angel Zaballos, Juana M Flores, Mariano Barbacid, David Beach, Manuel Serrano
Nature 2005-08-04
Oncogene-induced senescence is a cellular response that may be crucial for protection against cancer development, but its investigation has so far been restricted to cultured cells that have been manipulated to overexpress an oncogene. Here we analyse tumours initiated by an endogenous oncogene, ras, and show that senescent cell...阅读更多
Zhenbang Chen, Lloyd C Trotman, David Shaffer, Hui-Kuan Lin, Zohar A Dotan, Masaru Niki, Jason A Koutcher, Howard I Scher, Thomas Ludwig, William Gerald, Carlos Cordon-Cardo, Pier Paolo Pandolfi
Nature 2005-08-04
Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cance...阅读更多
Chrysiis Michaloglou, Liesbeth C W Vredeveld, Maria S Soengas, Christophe Denoyelle, Thomas Kuilman, Chantal M A M van der Horst, Donné M Majoor, Jerry W Shay, Wolter J Mooi, Daniel S Peeper
Nature 2005-08-04
Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited pre...阅读更多
Melanie Braig, Soyoung Lee, Christoph Loddenkemper, Cornelia Rudolph, Antoine H F M Peters, Brigitte Schlegelberger, Harald Stein, Bernd Dörken, Thomas Jenuwein, Clemens A Schmitt
Nature 2005-08-04
Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) wa...阅读更多
A L Jackson, L A Loeb
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2001-06-02
There is increasing evidence that most human cancers contain multiple mutations. By the time a tumor is clinically detectable it may have accumulated tens of thousands of mutations. In normal cells, mutations are rare events occurring at a rate of 10(-10) mutations per nucleotide per cell per generation. We have argued that the ...阅读更多
Rinne De Bont, Nik van Larebeke
Mutagenesis 2004-05-01
DNA damage plays a major role in mutagenesis, carcinogenesis and ageing. The vast majority of mutations in human tissues are certainly of endogenous origin. A thorough knowledge of the types and prevalence of endogenous DNA damage is thus essential for an understanding of the interactions of endogenous processes with exogenous a...阅读更多
T Lindahl, B Nyberg
Biochemistry (Washington) 1972-09-12
Reto Brem, Janet Hall
Nucleic Acids Research 2005-01-01
The X-ray repair cross complementing 1 (XRCC1) protein is required for viability and efficient repair of DNA single-strand breaks (SSBs) in rodents. XRCC1-deficient mouse or hamster cells are hypersensitive to DNA damaging agents generating SSBs and display genetic instability after such DNA damage. The presence of certain polym...阅读更多
Suryakant K Niture, Chinavenmani S Velu, Quentin R Smith, G Jayarama Bhat, Kalkunte S Srivenugopal
Carcinogenesis 2007-02-01
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which protects the cellular genome and critical oncogenic genes from the mutagenic action of endogenous and exogenous alkylating agents. An expedited elimination of O6-alkylguanines by increasing MGMT activity levels is likely to be a successful chemopreventio...阅读更多
Robert E Goldsby, Laura E Hays, Xin Chen, Elise A Olmsted, William B Slayton, Gerry J Spangrude, Bradley D Preston
PNAS 2002-11-26
Mutations are a hallmark of cancer. Normal cells minimize spontaneous mutations through the combined actions of polymerase base selectivity, 3' --> 5' exonucleolytic proofreading, mismatch correction, and DNA damage repair. To determine the consequences of defective proofreading in mammals, we created mice with a point mutation ...阅读更多
W Yang
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2000-08-30
DNA mismatch repair is required for maintaining genomic stability and is highly conserved from prokaryotes to eukaryotes. Errors made during DNA replication, such as deletions, insertions and mismatched basepairs, are substrates for mismatch repair. Mismatch repair is strand-specific and targets only the newly synthesized daught...阅读更多
Ravi R Iyer, Anna Pluciennik, Vickers Burdett, Paul L Modrich
Chemical Reviews 2006-02-01
Paul Modrich
Journal of Biological Chemistry 2006-10-13
Annegret Müller, Richard Fishel
Cancer Investigation 2002-01-01
The hereditary non-polyposis colorectal cancer (HNPCC)-syndrome is the most common form of hereditary colorectal cancers, and accounts for 2-7% of the total colorectal cancer burden. Since there are no single clinical features specific for HNPCC, diagnosis is based on family history (Amsterdam or Bethesda criteria) and is confir...阅读更多
T Lindahl
PNAS 1974-09-01
An enzyme that liberates uracil from single-stranded and double-stranded DNA containing deaminated cytosine residues and from deoxycytidylate-deoxyuridylate copolymers in the absence of Mg(++) has been purified 30-fold from cell extracts of E. coli. The enzyme does not release uracil from deoxyuridine, dUMP, uridine, or RNA, nor...阅读更多
B Singer, B Hang
Chemical Research in Toxicology 1997-07-01
A crucial question in repair is how do enzymes recognize substrates. In surveying the relevant literature, it becomes evident that there are no rules which can be clearly applied. At this time it appears that uracil glycosylase is the only repair enzyme for which all the known substrates can be rationalized on the basis of chemi...阅读更多
T Lindahl, R D Wood
Science 1999-12-03
Faithful maintenance of the genome is crucial to the individual and to species. DNA damage arises from both endogenous sources such as water and oxygen and exogenous sources such as sunlight and tobacco smoke. In human cells, base alterations are generally removed by excision repair pathways that counteract the mutagenic effects...阅读更多
K W Caldecott, S Aoufouchi, P Johnson, S Shall
Nucleic Acids Research 1996-11-15
The DNA repair proteins XRCC1 and DNA ligase III are physically associated in human cells and directly interact in vitro and in vivo. Here, we demonstrate that XRCC1 is additionally associated with DNA polymerase-beta in human cells and that these polypeptides also directly interact. We also present data suggesting that poly (AD...阅读更多
F Dantzer, G de La Rubia, J Ménissier-De Murcia, Z Hostomsky, G de Murcia, V Schreiber
Biochemistry (Washington) 2000-06-27
In mammalian cells, damaged bases in DNA are corrected by the base excision repair pathway which is divided into two distinct pathways depending on the length of the resynthesized patch, replacement of one nucleotide for short-patch repair, and resynthesis of several nucleotides for long-patch repair. The involvement of poly(ADP...阅读更多
D K Srivastava, B J Berg, R Prasad, J T Molina, W A Beard, A E Tomkinson, S H Wilson
Journal of Biological Chemistry 1998-08-14
Base excision repair (BER) is one of the cellular defense mechanisms repairing damage to nucleoside 5'-monophosphate residues in genomic DNA. This repair pathway is initiated by spontaneous or enzymatic N-glycosidic bond cleavage creating an abasic or apurinic-apyrimidinic (AP) site in double-stranded DNA. Class II AP endonuclea...阅读更多
Tamara A Ranalli, Samson Tom, Robert A Bambara
Journal of Biological Chemistry 2002-11-01
Base loss is common in cellular DNA, resulting from spontaneous degradation and enzymatic removal of damaged bases. Apurinic/apyrimidinic (AP) endonucleases recognize and cleave abasic (AP) sites during base excision repair (BER). APE1 (REF1, HAP1) is the predominant AP endonuclease in mammalian cells. Here we analyzed the influ...阅读更多
Ulrike Sattler, Philippe Frit, Bernard Salles, Patrick Calsou
EMBO Reports 2003-04-01
The base excision repair (BER) process removes base damage such as oxidation, alkylation or abasic sites. Two BER sub-pathways have been characterized using in vitro methods, and have been classified according to the length of the repair patch as either 'short-patch' BER (one nucleotide) or 'long-patch' BER (LP-BER; more than on...阅读更多
P Fortini, B Pascucci, E Parlanti, R W Sobol, S H Wilson, E Dogliotti
Biochemistry (Washington) 1998-03-17
Mammalian cells possess two distinct pathways for completion of base excision repair (BER): the DNA polymerase beta (Pol beta)-dependent short-patch pathway (replacement of one nucleotide), which is the main route, and the long-patch pathway (resynthesis of 2-6 nucleotides), which is PCNA-dependent. To address the issue of how t...阅读更多
A Klungland, T Lindahl
EMBO Journal 1997-06-02
Two forms of DNA base excision-repair (BER) have been observed: a 'short-patch' BER pathway involving replacement of one nucleotide and a 'long-patch' BER pathway with gap-filling of several nucleotides. The latter mode of repair has been investigated using human cell-free extracts or purified proteins. Correction of a regular a...阅读更多
Jung-Suk Sung, Bruce Demple
FEBS Journal 2006-04-01
Base excision DNA repair (BER) is fundamentally important in handling diverse lesions produced as a result of the intrinsic instability of DNA or by various endogenous and exogenous reactive species. Defects in the BER process have been associated with cancer susceptibility and neurodegenerative disorders. BER funnels diverse ba...阅读更多
A S Balajee, V A Bohr
Gene 2000-05-30
Nucleotide excision repair (NER) is one of the major cellular pathways that removes bulky DNA adducts and helix-distorting lesions. The biological consequences of defective NER in humans include UV-light-induced skin carcinogenesis and extensive neurodegeneration. Understanding the mechanism of the NER process is of great import...阅读更多
Laurent Gros, Murat K Saparbaev, Jacques Laval
Oncogene 2002-12-16
A number of intrinsic and extrinsic mutagens induce structural damage in cellular DNA. These DNA damages are cytotoxic, miscoding or both and are believed to be at the origin of cell lethality, tissue degeneration, ageing and cancer. In order to counteract immediately the deleterious effects of such lesions, leading to genomic i...阅读更多
Jin-Sam You, Mu Wang, Suk-Hee Lee
Journal of Biological Chemistry 2003-02-28
XPA, XPC-hHR23B, RPA, and TFIIH all are the damage recognition proteins essential for the early stage of nucleotide excision repair. Nonetheless, it is not clear how these proteins work together at the damaged DNA site. To get insight into the molecular mechanism of damage recognition, we carried out a comprehensive analysis on ...阅读更多
Rafael Rosell, Miguel Taron, Agusti Barnadas, Giorgio Scagliotti, Carme Sarries, Barbara Roig
Cancer Control 2003-01-01
In spite of the growing list of genetic abnormalities identified as being involved in DNA repair pathways that alter chemosensitivity in non-small-cell lung cancer (NSCLC) patients, translational assays have not yet been developed for use in individualized chemotherapy. In metastatic NSCLC, no single cisplatin-based chemotherapy...阅读更多
U Vogel, M Dybdahl, G Frentz, B A Nexo
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2000-11-09
We have previously shown that high DNA repair capacity protects psoriasis patients against chemically induced basal cell carcinoma [Dybdahl et al. Mutat. Res. 433 (1999) 15-22]. We have used the same study persons to investigate the correlation between expression of eight genes involved in nucleotide excision repair and DNA repa...阅读更多
Philip C Hanawalt
Oncogene 2002-12-16
Nucleotide excision repair provides an important cellular defense against a large variety of structurally unrelated DNA alterations. Most of these alterations, if unrepaired, may contribute to mutagenesis, oncogenesis, and developmental abnormalities, as well as cellular lethality. There are two subpathways of nucleotide excisio...阅读更多
S E Critchlow, S P Jackson
Trends in Biochemical Sciences 1998-10-01
DNA non-homologous end-joining (NHEJ) is a crucial process that has been conserved highly throughout eukaryotic evolution. At its heart is a multiprotein complex containing the KU70-KU80 heterodimer. Recent work has identified additional proteins involved in this pathway, providing insights into the mechanism of NHEJ and reveali...阅读更多
Huichen Wang, Ange Ronel Perrault, Yoshihiko Takeda, Wei Qin, Hongyan Wang, George Iliakis
Nucleic Acids Research 2003-09-15
Cells of higher eukaryotes process within minutes double strand breaks (DSBs) in their genome using a non-homologous end joining (NHEJ) apparatus that engages DNA-PKcs, Ku, DNA ligase IV, XRCC4 and other as of yet unidentified factors. Although chemical inhibition, or mutation, in any of these factors delays processing, cells ul...阅读更多
Ronel Perrault, Huichen Wang, Minli Wang, Bustanur Rosidi, George Iliakis
Journal of Cellular Biochemistry 2004-07-01
In cells of higher eukaryotes double strand breaks (DSBs) induced in the DNA after exposure to ionizing radiation (IR) are rapidly rejoined by a pathway of non-homologous end joining (NHEJ) that requires DNA dependent protein kinase (DNA-PK) and is therefore termed here D-NHEJ. When this pathway is chemically or genetically inac...阅读更多
Isabel Sánchez-Pérez
Clinical & Translational Oncology 2006-09-01
Chemotherapy and radiation are two important modalities for cancer treatment. Many agents in clinical used have the ability to induce DNA damage, however they may be highly cytotoxic as a secondary effect. Different mechanisms are involved both, in detection and repair of DNA damage. The modulation of these pathways, has a great...阅读更多
Srinivasan Madhusudan, Ian D Hickson
Trends in Molecular Medicine 2005-11-01
Advanced cancer is a leading cause of death in the developed world. Chemotherapy and radiation are the two main treatment modalities currently available. The cytotoxicity of many of these agents is directly related to their propensity to induce DNA damage. However, the ability of cancer cells to recognize this damage and initiat...阅读更多
Elizabeth Ruth Plummer
Current Opinion in Pharmacology 2006-08-01
Inhibition of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) has been extensively investigated in the pre-clinical setting as a strategy for chemo- or radio-potentiation. Recent evidence has suggested that PARP inhibitors might be active as single agents in certain rare inherited cancers that carry DNA repair defec...阅读更多
Ami Sabharwal, Mark R Middleton
Current Opinion in Pharmacology 2006-08-01
Improving the efficacy of standard chemotherapy by targeting DNA repair mechanisms remains an important area of research. O6-methylguanine-DNA-methyltransferase (MGMT), which repairs alkylating agent damage, is one such target. Downregulation of the gene through epigenetic silencing has been shown to predict response to alkylati...阅读更多