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【medical-news】DNA修复途径中的关键酶与卵巢癌等的关系

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http://www.sciencedaily.com/releases/2010/07/100729141138.htm

Key Enzyme in DNA Repair Pathway Identified

ScienceDaily (July 29, 2010) — Researchers have discovered an enzyme crucial to a type of DNA repair that also causes resistance to a class of cancer drugs most commonly used against ovarian cancer.

Scientists from The University of Texas MD Anderson Cancer Center and the Life Sciences Institute of Zhejiang University in China report the discovery of the enzyme and its role in repairing DNA damage called cross-linking in the Science Express advance online publication of Science.

"This pathway that repairs cross-linking damage is a common factor in a variety of cancers, including breast cancer and especially in ovarian cancer. If the pathway is active, it undoes the therapeutic effect of cisplatin and similar therapies," said co-corresponding author Junjie Chen, Ph.D., professor and chair of MD Anderson's Department of Experimental Radiation Oncology.

The platinum-based chemotherapies cisplatin, carboplatin and oxaliplatin work by causing DNA cross-linking in cancer cells, which blocks their ability to divide and leads to cell death. Cross-linking occurs when one of the two strands of DNA in a cell branches out and links to the other strand.

Cisplatin and similar drugs are often initially effective against ovarian cancer, Chen said, but over time the disease becomes resistant and progresses.

Scientists have known that the protein complex known as FANCI-FANCD2 responds to DNA damage and repairs cross-linking, but the details of how the complex works have been unknown. "The breakthrough in this research is that we finally found an enzyme involved in the repair process," Chen said.

The enzyme, which they named FAN1, appears to be a nuclease, which is capable of slicing through strands of DNA.

In a series of experiments, Chen and colleagues demonstrated how the protein complex summons FAN1, connects with the enzyme and moves it to the site of DNA cross-linking. They also showed that FAN1 cleaves branched DNA but leaves the normal, separate double-stranded DNA alone. Mutant versions of FAN1 were unable to slice branched DNA.

Like a lock and key

The researchers also demonstrated that FAN1 cannot get at DNA damage without being taken there by the FANCI-FANCD2 protein complex, which detects and moves to the damaged site. The complex recruits the FAN1 enzyme by acquiring a single ubiquitin molecule. FAN1 connects with the complex by binding to the ubiquitin site.

"It's like a lock and key system, once they fit, FAN1 is recruited," Chen said.

Analyzing the activity of this repair pathway could guide treatment for cancer patients, Chen said, with the platinum-based therapies used when the cross-linking repair mechanism is less active.

Scientists had shown previously that DNA repair was much less efficient when FANCI and FANCD2 lack the single ubiquitin. DNA response and damage-repair proteins can be recruited to damage sites by the proteins' ubiquitin-binding domains. The team first identified a protein that had both a ubiquitin-binding domain and a known nuclease domain. When they treated cells with mitomycin C, which promotes DNA cross-linking, that protein, then known as KIAA1018, gathered at damage sites. This led them to the functional experiments that established its role in DNA repair.

They renamed the protein FAN1, short for Fanconi anemia-associated nuclease 1. The FANCI-FANCD2 complex is ubiquitinated by an FA core complex containing eight FA proteins. These genes and proteins were discovered during research of Fanconi anemia, a rare disease caused by mutations in 13 fanc genes that is characterized by congenital malformations, bone marrow failure, cancer and hypersensitivity to DNA cross-linking agents.

Chen said the FANCI-FANCD2 pathway also is associated with the BRCA1 and BRCA2 pathways, which are involved in homologous recombination repair. Scientists know that homologous recombination repair is also required for the repair of DNA cross-links, but the exact details remain to be resolved, Chen said. Mutations to BRCA1 and BRCA2 are known to raise a woman's risk for ovarian and breast cancers and are found in about 5-10 percent of women with either disease.

Co-authors with Chen are co-first author Gargi Ghosal, Ph.D., and Jingsong Yuan, Ph.D., also of Experimental Radiation Oncology at MD Anderson; and co-corresponding author Jun Huang, Ph.D., co-first author Ting Liu, Ph.D., of the Life Sciences Institute of Zhejiang University in Hangzhou, China.

This research was funded by a grant from the U.S. National Institutes of Health and the Startup Fund at Zhejiang University.

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Key Enzyme in DNA Repair Pathway Identified
DNA修复途径中的关键酶
ScienceDaily (July 29, 2010) — Researchers have discovered an enzyme crucial to a type of DNA repair that also causes resistance to a class of cancer drugs most commonly used against ovarian cancer.
据2010年7月29日的科学日报称，科研人员发现了一种新的DNA修复关键酶，该关键酶能对一大类抗癌药物产生耐药，这其中最主要的是治疗卵巢癌的药物。
Scientists from The University of Texas MD Anderson Cancer Center and the Life Sciences Institute of Zhejiang University in China report the discovery of the enzyme and its role in repairing DNA damage called cross-linking in the Science Express advance online publication of Science.
来自美国德克萨斯大学安德森肿瘤中心和中国浙江大学生命科学研究所的科学家在《科学快报》杂志上发表了一篇报道，报道揭示了该酶的发现，及其对被称为交联的DNA损坏的修复功能，《科学快报》杂志先于《科学》杂志在线发行。
"This pathway that repairs cross-linking damage is a common factor in a variety of cancers, including breast cancer and especially in ovarian cancer. If the pathway is active, it undoes the therapeutic effect of cisplatin and similar therapies," said co-corresponding author Junjie Chen, Ph.D., professor and chair of MD Anderson's Department of Experimental Radiation Oncology.
合作通讯作者之一，博士，教授，MD Anderson实验放射肿瘤专业客座教授Junjie Chen教授说：“修复交联损坏的途径是各种肿瘤常见的作用机制，包括在乳腺癌，尤其在卵巢癌。如果这个途径被激活，它能使诸如顺铂等类似药物的抗癌作用失效。”
The platinum-based chemotherapies cisplatin, carboplatin and oxaliplatin work by causing DNA cross-linking in cancer cells, which blocks their ability to divide and leads to cell death. Cross-linking occurs when one of the two strands of DNA in a cell branches out and links to the other strand.
以铂为基本结构的化疗药物如顺铂、碳铂、奥克赛铂等，它们的作用原理是通过引起癌细胞DNA发生交联反应，阻止癌细胞分裂，进而导致其死亡。当细胞内DNA两条核苷酸链中的一条发生分叉，并与其它核苷酸发生耦连时，交联现象往往就会发生。
Cisplatin and similar drugs are often initially effective against ovarian cancer, Chen said, but over time the disease becomes resistant and progresses.
Junjie Chen教授表示，顺铂及其同类药物在治疗卵巢癌起初常常有效，但不久之后，就会出现耐药，病情也随之恶化。
Scientists have known that the protein complex known as FANCI-FANCD2 responds to DNA damage and repairs cross-linking, but the details of how the complex works have been unknown. "The breakthrough in this research is that we finally found an enzyme involved in the repair process," Chen said.
科学家早已确信存在一种称为FANCI-FANCD2的蛋白复合物，该复合体与DNA损伤及交联修复有并，至于其作用机制尚未可知。Junjie Chen教授说道：“该项研究的突破就是我们最终发现了一种与修复过程有关的酶。”
The enzyme, which they named FAN1, appears to be a nuclease, which is capable of slicing through strands of DNA.
目前发现的这个酶被命名为FAN1，它是一种核酸酶，能够切割开DNA的核苷酸链。
In a series of experiments, Chen and colleagues demonstrated how the protein complex summons FAN1, connects with the enzyme and moves it to the site of DNA cross-linking. They also showed that FAN1 cleaves branched DNA but leaves the normal, separate double-stranded DNA alone. Mutant versions of FAN1 were unable to slice branched DNA.
经过多次实验，Junjie Chen教授及其同事阐明了蛋白复合体如何趋化FAN1，如何与之连接，并进而驱动FAN1至DNA交联的位置。科研小组还进一步揭示了FAN1如何切割开已发生了分枝的DNA，却并不影响正常的双股螺旋DNA结构的过程。如果FAN1发生了突变，也就随即失去切割分枝DNA的能力。
Like a lock and key
就象一把锁与一把钥匙的关系
The researchers also demonstrated that FAN1 cannot get at DNA damage without being taken there by the FANCI-FANCD2 protein complex, which detects and moves to the damaged site. The complex recruits the FAN1 enzyme by acquiring a single ubiquitin molecule. FAN1 connects with the complex by binding to the ubiquitin site.
科研人员还进一步证明，如果没有被FANCI-FANCD2蛋白复合体发现、驱动至相应的位置，FAN1就不能造成DNA的损伤。该蛋白复合体通过获取一种单泛素分子趋化FAN1， FAN1则是通过与蛋白复合体的泛素位点粘合而发生连接。
"It's like a lock and key system, once they fit, FAN1 is recruited," Chen said.
Junjie Chen教授说，“这就象一把锁配一把钥匙，一旦两者匹配，FAN1就趋化发生作用。”
Analyzing the activity of this repair pathway could guide treatment for cancer patients, Chen said, with the platinum-based therapies used when the cross-linking repair mechanism is less active.
Junjie Chen教授认为，对这个修复过程的分析将有助于指导肿瘤患者的治疗，比如，若肿瘤细胞交联修复处于相对静息状态，就可以使用以铂为基本结构的化疗药物对患者进行治疗。
Scientists had shown previously that DNA repair was much less efficient when FANCI and FANCD2 lack the single ubiquitin. DNA response and damage-repair proteins can be recruited to damage sites by the proteins' ubiquitin-binding domains. The team first identified a protein that had both a ubiquitin-binding domain and a known nuclease domain. When they treated cells with mitomycin C, which promotes DNA cross-linking, that protein, then known as KIAA1018, gathered at damage sites. This led them to the functional experiments that established its role in DNA repair.
在此之前，科学家就已清楚，在FANCI和FANCD2缺少单泛素时，DNA修复基本无效。在蛋白的泛素结合区域的作用下，DNA应答及损伤修复蛋白会趋化至损伤位置。该研究小组首次证实存在有一种蛋白质，命名为KIAA1018，该蛋白质既有泛素结合区域，还有已知的核酸酶区域。当科研人员为了提高细胞内的DNA交联，用丝裂霉素C对细胞进行处理，结果发现，KIAA1018蛋白聚集在损伤位置。这个现象引导科研人员进行了进一步的实验，以明确其在DNA修复中的作用原理。
They renamed the protein FAN1, short for Fanconi anemia-associated nuclease 1. The FANCI-FANCD2 complex is ubiquitinated by an FA core complex containing eight FA proteins. These genes and proteins were discovered during research of Fanconi anemia, a rare disease caused by mutations in 13 fanc genes that is characterized by congenital malformations, bone marrow failure, cancer and hypersensitivity to DNA cross-linking agents.
科研人员重命名该蛋白质为FAN1，是Fanconi贫血相关核酸酶1的缩写形式。FANCI-FANCD2复合体在包含8种叶酸蛋白质的叶酸核复合体作用下泛素化，这些基因和蛋白质是在研究范可尼贫血过程中发现的，范可尼贫血是一种罕见的疾病，由人体13 fanc基因突变所致，特征性的表现有先天性畸形、骨髓衰竭、癌症、DNA交联剂的高敏感性等。
Chen said the FANCI-FANCD2 pathway also is associated with the BRCA1 and BRCA2 pathways, which are involved in homologous recombination repair. Scientists know that homologous recombination repair is also required for the repair of DNA cross-links, but the exact details remain to be resolved, Chen said. Mutations to BRCA1 and BRCA2 are known to raise a woman's risk for ovarian and breast cancers and are found in about 5-10 percent of women with either disease.
Junjie Chen教授表示，FANCI-FANCD2途径也与BRCA1和BRCA2途径有关，这涉及同源生物再结合修复。科学家知道，DNA交联修复过程中也需要同源生物再结合修复参与，但是精确的细节仍有待研究。目前已知BRCA1和BRCA2的突变能增加妇女罹患卵巢癌和乳腺癌的风险，并且已经查明，在大约为5-10%妇女中，会罹患卵巢癌或者乳腺癌。
Co-authors with Chen are co-first author Gargi Ghosal, Ph.D., and Jingsong Yuan, Ph.D., also of Experimental Radiation Oncology at MD Anderson; and co-corresponding author Jun Huang, Ph.D., co-first author Ting Liu, Ph.D., of the Life Sciences Institute of Zhejiang University in Hangzhou, China.
Junjie Chen教授合作的作者有：第一合作作者Gargi Ghosal博士，Jingsong Yuan博士，这两位也工作于MD Anderson实验放射肿瘤专业；合作通讯作者Jun Huang博士，第一合作作者Ting Liu博士，后两位工作于中国浙江大学生命科学研究所。
This research was funded by a grant from the U.S. National Institutes of Health and the Startup Fund at Zhejiang University.
该项研究受到美国国家健康研究所及浙江大学启动基金的支持。

编译（约1480字）
DNA修复途径中的关键酶
据2010年7月29日的科学日报称，科研人员发现了一种新的DNA修复关键酶，该关键酶能对一大类抗癌药物产生耐药，这其中最主要的是治疗卵巢癌的药物。
来自美国德克萨斯大学安德森肿瘤中心和中国浙江大学生命科学研究所的科学家在《科学快报》杂志上发表了一篇报道，报道揭示了该酶的发现，及其对被称为交联的DNA损坏的修复功能，《科学快报》杂志先于《科学》杂志在线发行。
合作通讯作者之一，博士，教授，MD Anderson实验放射肿瘤专业客座教授Junjie Chen教授说：“修复交联损坏的途径是各种肿瘤常见的作用机制，包括在乳腺癌，尤其在卵巢癌。如果这个途径被激活，它能使诸如顺铂等类似药物的抗癌作用失效。”
以铂为基本结构的化疗药物如顺铂、碳铂、奥克赛铂等，它们的作用原理是通过引起癌细胞DNA发生交联反应，阻止癌细胞分裂，进而导致其死亡。当细胞内DNA两条核苷酸链中的一条发生分叉，并与其它核苷酸发生耦连时，交联现象往往就会发生。
Junjie Chen教授表示，顺铂及其同类药物在治疗卵巢癌起初常常有效，但不久之后，就会出现耐药，病情也随之恶化。
科学家早已确信存在一种称为FANCI-FANCD2的蛋白复合物，该复合体与DNA损伤及交联修复有并，至于其作用机制尚未可知。Junjie Chen教授说道：“该项研究的突破就是我们最终发现了一种与修复过程有关的酶。”
目前发现的这个酶被命名为FAN1，它是一种核酸酶，能够切割开DNA的核苷酸链。
经过多次实验，Junjie Chen教授及其同事阐明了蛋白复合体如何趋化FAN1，如何与之连接，并进而驱动FAN1至DNA交联的位置。科研小组还进一步揭示了FAN1如何切割开已发生了分枝的DNA，却并不影响正常的双股螺旋DNA结构的过程。如果FAN1发生了突变，也就随即失去切割分枝DNA的能力。
就象一把锁与一把钥匙的关系
科研人员还进一步证明，如果没有被FANCI-FANCD2蛋白复合体发现、驱动至相应的位置，FAN1就不能造成DNA的损伤。该蛋白复合体通过获取一种单泛素分子趋化FAN1， FAN1则是通过与蛋白复合体的泛素位点粘合而发生连接。
Junjie Chen教授说，“这就象一把锁配一把钥匙，一旦两者匹配，FAN1就趋化发生作用。”
Junjie Chen教授认为，对这个修复过程的分析将有助于指导肿瘤患者的治疗，比如，若肿瘤细胞交联修复处于相对静息状态，就可以使用以铂为基本结构的化疗药物对患者进行治疗。
在此之前，科学家就已清楚，在FANCI和FANCD2缺少单泛素时，DNA修复基本无效。在蛋白的泛素结合区域的作用下，DNA应答及损伤修复蛋白会趋化至损伤位置。该研究小组首次证实存在有一种蛋白质，命名为KIAA1018，该蛋白质既有泛素结合区域，还有已知的核酸酶区域。当科研人员为了提高细胞内的DNA交联，用丝裂霉素C对细胞进行处理，结果发现，KIAA1018蛋白聚集在损伤位置。这个现象引导科研人员进行了进一步的实验，以明确其在DNA修复中的作用原理。
科研人员重命名该蛋白质为FAN1，是Fanconi贫血相关核酸酶1的缩写形式。FANCI-FANCD2复合体在包含8种叶酸蛋白质的叶酸核复合体作用下泛素化，这些基因和蛋白质是在研究范可尼贫血过程中发现的，范可尼贫血是一种罕见的疾病，由人体13 fanc基因突变所致，特征性的表现有先天性畸形、骨髓衰竭、癌症、DNA交联剂的高敏感性等。
Junjie Chen教授表示，FANCI-FANCD2途径也与BRCA1和BRCA2途径有关，这涉及同源生物再结合修复。科学家知道，DNA交联修复过程中也需要同源生物再结合修复参与，但是精确的细节仍有待研究。目前已知BRCA1和BRCA2的突变能增加妇女罹患卵巢癌和乳腺癌的风险，并且已经查明，在大约为5-10%妇女中，会罹患卵巢癌或者乳腺癌。
Junjie Chen教授合作的作者有：第一合作作者Gargi Ghosal博士，Jingsong Yuan博士，这两位也工作于MD Anderson实验放射肿瘤专业；合作通讯作者Jun Huang博士，第一合作作者Ting Liu博士，后两位工作于中国浙江大学生命科学研究所。
该项研究受到美国国家健康研究所及浙江大学启动基金的支持。

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2010-08-03 21:51

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