更新于：2024-11-01

LIG3

更新于：2024-11-01

基本信息

别名

DNA ligase 3、DNA ligase III、LIG2

+ [3]

简介

Isoform 3 functions as heterodimer with DNA-repair protein XRCC1 in the nucleus and can correct defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents. Isoform 1 is targeted to mitochondria, where it functions as DNA ligase in mitochondrial base-excision DNA repair (PubMed:10207110, PubMed:24674627).

关联

100 项与 LIG3 相关的临床结果

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100 项与 LIG3 相关的转化医学

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0 项与 LIG3 相关的专利（医药）

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350

项与 LIG3 相关的文献（医药）

2024-12-01·Journal of Central Nervous System Disease

Meningoencephalitis in a novel mutation in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) ending a familial diagnostic odyssey: A case series report

Article

作者: Humaidan, Hani ; Ghareeb, Sara ; Hasan, Hasan ; Al-Sahlawi, Zahra ; Redha, Noor

MNGIE (Mitochondrial Neurogastrointestinal Encephalomyopathy) is an ultra-rare autosomal recessive disorder that leads to mutations in the nuclear genes encoding thymidine phosphorylase. Symptoms include gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoplegia, sensorimotor neuropathy and asymptomatic leukoencephalopathy. We describe the first case of MNGIE with meningoencephalitis that ultimately led to a familial diagnosis ending a diagnostic odyssey. We retrospectively reviewed the electronic medical records and sent whole exome sequencing for the index case and his family members. We report the variant c.877T>C p.(Cys293Arg) found in TYMP gene in all affected siblings showed typical clinical manifestations related to MNGIE. To the best of our knowledge, this is not described in the literature nor in the population databases dbSNP (Single Nucleotide Polymorphism Database) and gnomAD (Genome Aggregation Database). Additionally, it is located in a highly conserved residue and the bioinformatic analysis suggests it is most probably deleterious. Moreover, we estimated 550 number of cases of MNGIE (including 5 cases in this study) after performing an extensive search in the literature across 3 databases from 1983-2023. In addition, we identified 44 patients with MNGIE-like phenotype in genes other than TYMP. MNGIE-like phenotype affects POLG1, RRM2B, LIG3, RRM1, MTTV1, and MT-RNR1 genes.

2024-10-01·Journal of Biological Chemistry

CDK-Dependent Phosphorylation Regulates PNKP Function in DNA Replication

Article

作者: Fanta, Mesfin ; Li, Lei ; Zeinali, Elham ; Godbout, Roseline ; Ismail, Ismail Hassan ; Ganje, Cassandra ; Mashayekhi, Fatemeh ; Weinfeld, Michael

Okazaki fragment maturation (OFM) stands as a pivotal DNA metabolic process, crucial for genome integrity and cell viability. Dysregulation of OFM leads to DNA single-strand breaks- accumulation, which is linked to various human diseases such as cancer and neurodegenerative disorders. Recent studies have implicated LIG3-XRCC1 acting in an alternative OFM pathway to the canonical FEN1-LIG1 pathway. Here, we reveal that polynucleotide kinase-phosphatase (PNKP) is another key participant in DNA replication, akin to LIG3-XRCC1. Through functional experiments, we demonstrate PNKP's enrichment at DNA replication forks and its association with PCNA, indicating its involvement in replication processes. Cellular depletion of PNKP mirrors defects observed in OFM-related proteins, highlighting its significance in replication fork dynamics. Additionally, we identify PNKP as a substrate for cyclin-dependent kinase 1/2 (CDK1/2), which phosphorylates PNKP at multiple residues. Mutation analysis of these phosphorylation sites underscores the importance of CDK2-mediated PNKP phosphorylation in DNA replication. Our findings collectively indicate a novel role for PNKP in facilitating Okazaki fragment joining, thus shedding light on its contribution to genome stability maintenance.

2024-09-01·Molecular Neurobiology

Histone Methyltransferase G9a Plays an Essential Role on Nicotine Preference in Zebrafish

Article

作者: Rocco, Leandro ; Ortiz, Joaquin ; Faillace, Maria Paula ; Bernabeu, Ramon

Psychostimulants regulate behavioral responses in zebrafish via epigenetic mechanisms. We have previously shown that DNA methylation and histone deacetylase (HDAC) inhibition abolish nicotine-induced conditioned place preference (CPP) but little is known about the role of histone methylation in addictive-like behaviors. To assess the influence of histone methylation on nicotine-CPP, zebrafish were treated with a histone (H3) lysine-9 (K9) dimethyltransferase G9a/GLP inhibitor, BIX-01294 (BIX), which was administered before conditioning sessions. We observed a dual effect of the inhibitor BIX: at high doses inhibited while at low doses potentiated nicotine reward. Transcriptional expression of α6 and α7 subunits of the nicotinic acetylcholine receptor and of G9a, DNA methyl transferase-3, and HDAC-1 was upregulated in zebrafish with positive scores for nicotine-CPP. Changes in relative levels of these mRNA molecules reflected the effects of BIX on nicotine reward. BIX treatment per sé did not affect transcriptional levels of epigenetic enzymes that regulate trimethylation or demethylation of H3. BIX reduced H3K9me2 protein levels in a dose-dependent manner in key structures of the reward pathway. Thus, our findings indicated that different doses of BIX differentially affect nicotine CPP via strong or weak inhibition of G9a/GLP activity. Additionally, we found that the lysine demethylase inhibitor daminozide abolished nicotine-CPP and drug seeking. Our data demonstrate that H3 methylation catalyzed by G9a/GLP is involved in nicotine-CPP induction. Dimethylation of K9 at H3 is an important epigenetic modification that should be considered as a potential therapeutic target to treat nicotine reward and perhaps other drug addictions.

项与 LIG3 相关的新闻（医药）

2024-10-13

·生物探索

Mol Cell | 查珊团队揭示PARP2失活引起PARP抑制剂相关的血液学副作用

引言聚ADP-ribose聚合酶 (Poly ADP-ribose polymerase) PARP1和PARP2催化的ADP-ribose 聚合作用（PARylation）参与多种的生理过程，尤其是在DNA损伤修复的过程中有重要的作用。由PARP1/2介导的以及BRCT1/2介导的两种不同的DNA损伤修复存在有协同作用，共同保证了组织细胞基因组的完整性。基于合成致死的概念，临床中PARP抑制剂被广泛应用了靶向治疗BRCA1/2突变的癌症，其能够在特异性杀死BRCA1/2突变的癌细胞的同时不对正常细胞产生影响。目前，FDA已经批准了四种PARP抑制剂用于治疗BRCA1/2突变的癌症。虽然它们在治疗中显示出巨大潜力，但最近由于无法解释的严重血液学副作用，包括贫血和药物相关的白血病，限制了其使用。在2022年，其中两种PARP抑制剂就因位会导致严重贫血和增加治疗相关髓性白血病的风险而被FDA撤回用于维持治疗的批准。目前用于临床的四种PARP抑制剂均为PARP1和PARP2的双重抑制剂。他们不仅能够同时抑制PARP1 和PARP2 的酶活性，同时还能够将PARP1 和PARP2滞留在DNA损伤位点上。大量的研究表明，PARP1的滞留对于PARP 抑制剂的癌症治疗效果是至关重要的。敲除PAPR1会极大的降低癌症细胞对PARP抑制剂的敏感性。然而，敲除PARP2却没有任何的影响。对于PARP2失活所带来的的生理学的后果仍然缺少有效的研究。 2024年10月8日，来自美国的哥伦比亚大学查珊团队在Molecular Cell期刊上发表了题为Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts的研究论文，文章表明失去活性的PARP2可能是引起PARP抑制剂相关血液学副作用的因子。为了研究PAPR2失活所带来的生理学影响，研究人员通过同源重组的办法在小鼠染色体PARP2的基因原位引入了活性缺失的突变（PARP2-E534A）。E534A失活不仅能够有效的抑制Parp2活性，还能够将Parp2滞留在DNA损伤位点上。很好的模拟了PARP抑制剂作用下的Parp2。研究结果发现Parp2失活会导致小鼠胚胎致死。进一步分析胚胎发育，发现Parp2EA/EA的胚胎能够正常发育到E13.5左右时期。但是，这个时期的胚胎呈现出明显的红细胞生成障碍——与野生型的胚胎比较，Parp2EA/EA的胚胎缺乏血色以及更小更惨白胎肝（胚胎时期红细胞生成的器官）。作为比较，Parp2完全缺失的小鼠（Parp2-/-）能够正常的出生，且E13.5的胚胎没有明显的红细胞发生缺陷。表明失活的PARP2，而非其缺失，是导致小鼠出现致命性贫血的关键因素。研究还显示，失活的PARP2干扰DNA复制，引发基因组不稳定，并通过Tp53和Chk2依赖的通路导致细胞周期停滞和细胞凋亡。敲除Tp53或Chk2可逆转这些表型并挽救胚胎。有趣的是，该团队此前于2023年7月在《PNAS》上发表的研究指出，失活的PARP1也会导致小鼠胚胎死亡。但是其胚胎在E9.5之前就完全消失了，远早于胚胎红细胞生成的时间（E11.5）。表明失活的PARP2特异性阻碍红细胞的发生。这与PARP1和PARP2不同的DNA底物结合活性有关：PARP1能够通过其N端的3个锌指结构和WGR结构域结合到多种的DNA结构，包括单链DNA断裂（SSB），双链DNA 断裂（DSB）等；但是，PARP2的N端仅仅含有一个DNA结合结构域——WGR结构域。PARP2只能够结合并被5'-磷酸化DNA裂口（5’p-Nick）激活。在正常复制的细胞中，DNA滞后链的Okazaki片段成熟过程中会产生的大量的5’p-Nick需要通过DNA连接酶LIG1连接成完整的DNA。体外的5’p-Nick DNA连接实验表明，活性缺失的PARP2会抑制LIG1介导的连接作用。体内超分辨率荧光成像也表明失活的PARP2会阻碍LIG1结合到正在复制的DNA上。有意思的是，LIG1缺失的小鼠也呈现出相似胚胎致死性贫血表型，但其表型稍弱于Parp2EA/EA。进一步研究表明，Parp2-EA不仅能够抑制LIG1介导的连接作用，也同时能够抑制LIG3介导的连接作用。而LIG3已经被证明也能够在LIG1缺失的情况下参与Okazaki片段的连接。“失活的PARP2干扰了由LIG1和LIG3介导的关键DNA断裂连接，导致复制叉崩溃，”研究人员表示。“这种崩溃在具有超快速复制叉速度的红细胞母细胞中特别具有破坏性。”通过检测不同的组织细胞的PARylation水平，发现尽管DNA损伤通常会优先激活PARP1，但复制压力主要激活PARP2，揭示了PARP2在红细胞生成中的一个此前未知的复制特异性作用。综上所述，失活的PARP2选择性地结合并以变构方式滞留在5’p Nick处，干扰由LIG1和LIG3介导的Nick连接，包括冈崎片段的成熟。在依赖于及时处理冈崎片段的快速复制的红细胞母细胞中，失活的PARP2的存在会触发复制叉崩溃、DNA链断裂，最终引发依赖Tp53和Chk2的检查点激活、细胞凋亡和致命性贫血。临床上接受PARP抑制剂维持治疗的患者，可能因为长期造血压力而增加获得性Tp53和Chk2突变，进而提高患白血病的风险（图1）。该研究为当前PARP抑制剂相关的严重血液毒性提供了机制性解释，并揭示了PARP1和PARP2在DNA修复和复制中的功能差异，为进一步优化PARP抑制剂和其他DNA损伤应答抑制剂的治疗窗口提供了新思路。模式图（Credit: Molecular Cell）参考文献 https://www-cell-com.libproxy1.nus.edu.sg/molecular-cell/abstract/S1097-2765(24)00776-7 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床结果临床2期

2024-03-12

·BioSpace

InnoCare Announces Approval of Clinical Trial of BCL2 Inhibitor ICP-248 in Combination with Orelabrutinib as First-Line Therapy for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in China

BEIJING--(BUSINESS WIRE)-- InnoCare Pharma (HKEX: 09969; SSE: 688428), a leading biopharmaceutical company focusing on the treatment of cancer and autoimmune diseases, announced today the approval of the Investigational New Drug (IND) to conduct the clinical trial of B-cell lymphoma-2 (BCL2) inhibitor ICP-248 in combination with Bruton's tyrosine kinase (BTK) inhibitor orelabrutinib as first-line therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in China. This multicenter, randomized-controlled, open-label clinical study is designed to evaluate the efficacy and safety of ICP-248 combined with orelabrutinib versus immunochemotherapy in treatment-naive patients with CLL/SLL. ICP-248 is a novel, orally bioavailable BCL2-selective inhibitor, which aims to treat hematologic malignancies as a monotherapy or in combination with other therapies. BCL2 is an important regulatory protein of apoptosis pathway, and its abnormal expression is related to the development of various hematologic malignancies. ICP-248 has an anti-tumor effect by selectively inhibiting BCL2 and restoring the mechanism of programmed cell death. The preliminary result has demonstrated a good efficacy and safety profile. Orelabrutinib has been approved for marketing in China and Singapore, and all three approved indications related to lymphoma have been included in the National Reimbursement Drug List (NRDL) in China. In the treatment of relapsed/refractor CLL/SLL patients with orelabrutinib, the overall response rate and complete response rate reached 93.8% and 30% respectively, demonstrating an outstanding efficacy and safety profile. Dr. Jasmine Cui, the co-founder, chairwoman and CEO of InnoCare, said, "InnoCare has developed strong pipeline in hemato-oncology that covers a variety of important hemato-oncology targets, including BTK, BLC2, CD19, CD20xCD3, E-3 ligase, etc. ICP-248 and orelabrutinib are important global assets of our company in the field of hematology, with multiple clinical studies conducted in China and the United States. We will accelerate clinical development and look forward to providing CLL/SLL patients with more efficient and safe treatment options." CLL/SLL, one of the most common types of leukemia, is an indolent malignancy of B lymphocytes. There are 191,000 newly diagnosed CLL cases and 61,000 deaths every year globally1. The incidence rate of CLL/SLL is on the rise in China2. About InnoCare InnoCare is a commercial stage biopharmaceutical company committed to discovering, developing, and commercializing first-in-class and/or best-in-class drugs for the treatment of cancers and autoimmune diseases with unmet medical needs in China and worldwide. InnoCare has branches in Beijing, Nanjing, Shanghai, Guangzhou, Hong Kong, and the United States. InnoCare Forward-looking Statements This report contains the disclosure of some forward-looking statements. Except for statements of facts, all other statements can be regarded as forward-looking statements, that is, about our or our management's intentions, plans, beliefs, or expectations that will or may occur in the future. Such statements are assumptions and estimates made by our management based on its experience and knowledge of historical trends, current conditions, expected future development and other related factors. This forward-looking statement does not guarantee future performance, and actual results, development and business decisions may not match the expectations of the forward-looking statement. Our forward-looking statements are also subject to a large number of risks and uncertainties, which may affect our short-term and long-term performance. _________________________ 1 American Journal of Hematology 2 Ybanlv

临床申请临床研究上市批准ASH会议

2024-01-16

·BioSpace

InnoCare Announces Clearance of Clinical Trial of BCL2 Inhibitor ICP-248 by U.S. FDA

BEIJING--(BUSINESS WIRE)-- InnoCare Pharma (HKEX: 09969; SSE: 688428), a commercial-stage biotech company, announced today that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for the Company’s B-cell lymphoma-2 (BCL2) inhibitor, ICP-248. This is InnoCare’s fifth innovative drug to enter the clinical stage in the U.S. This is a Phase I study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of ICP-248 in hematologic malignancy patients. ICP-248 is a novel, orally bioavailable BCL2-selective inhibitor, which aims to treat hematologic malignancies as a monotherapy or in combination with other therapies. The Phase I dose escalation trial of ICP-248 is ongoing in China, and the preliminary results demonstrated good efficacy and safety pro BCL2 is an important regulatory protein of the apoptosis pathway, and its abnormal expression is related to the development of various hematologic malignancies. ICP-248 exhibits its anti-tumor effects by selectively inhibiting BCL2 and restoring the mechanism of programmed cell death. Dr. Jasmine Cui, the Co-founder, Chairwoman and CEO of InnoCare said, “ICP-248 would become an important asset for the Company’s globalization after orelabrutinib. The current study results will support ICP-248 to treat hematologic malignancies as a monotherapy or in combination with other therapies. Meanwhile, InnoCare is dedicated to building a leading franchise in hemato-oncology, and we have developed multiple drugs that cover a variety of important hemato-oncology targets such as BTK, CD19, CD20xCD3, BCL2 and E-3 ligase to address unmet medical needs.” About InnoCare InnoCare is a commercial stage biopharmaceutical company committed to discovering, developing, and commercializing first-in-class and/or best-in-class drugs for the treatment of cancers and autoimmune diseases with unmet medical needs in China and worldwide. InnoCare has branches in Beijing, Nanjing, Shanghai, Guangzhou, Hong Kong, and the United States. InnoCare Forward-looking Statements This report contains the disclosure of some forward-looking statements. Except for statements of facts, all other statements can be regarded as forward-looking statements, that is, about our or our management's intentions, plans, beliefs, or expectations that will or may occur in the future. Such statements are assumptions and estimates made by our management based on its experience and knowledge of historical trends, current conditions, expected future development and other related factors. This forward-looking statement does not guarantee future performance, and actual results, development and business decisions may not match the expectations of the forward-looking statement. Our forward-looking statements are also subject to a large number of risks and uncertainties, which may affect our short-term and long-term performance. View source version on businesswire.com: Contacts Media Chunhua Lu 86-10-66609879 chunhua.lu@innocarepharma.com Investors 86-10-66609999 ir@innocarepharma.com Source: InnoCare Pharma View this news release online at:

临床1期临床申请临床结果