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DNA ligase

Tomio S Takahashi, Yoshihiro Hirade, Aya Toma, Yusuke Sato, Atsushi Yamagata, Sakurako Goto-Ito, Akiko Tomita, Shinichiro Nakada, Shuya Fukai
The E3 ubiquitin (Ub) ligase RNF168 plays a critical role in the initiation of the DNA damage response to double-strand breaks (DSBs). The recruitment of RNF168 by ubiquitylated targets involves two distinct regions, Ub-dependent DSB recruitment module (UDM) 1 and UDM2. Here we report the crystal structures of the complex between UDM1 and Lys63-linked diUb (K63-Ub2) and that between the C-terminally truncated UDM2 (UDM2ΔC) and K63-Ub2. In both structures, UDM1 and UDM2ΔC fold as a single α-helix. Their simultaneous bindings to the distal and proximal Ub moieties provide specificity for Lys63-linked Ub chains...
January 12, 2018: Nature Communications
Karina Vázquez-Arreguín, Jessica Maddox, Jinsuk Kang, Dongju Park, Reuben R Cano, Rachel E Factor, Thomas Ludwig, Dean Tantin
The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with pro-glycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells towards a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype...
January 12, 2018: Molecular Cancer Research: MCR
Xiaosong Yang, You Pan, Zhaojun Qiu, Zhanwen Du, Yao Zhang, Pengyan Fa, Shashank Gorityala, Shanhuai Ma, Shunqiang Li, Ceshi Chen, Hongbing Wang, Yan Xu, Chunhong Yan, Ruth A Keri, Zhefu Ma, Junran Zhang
PURPOSE: 1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. EXPERIMENTAL DESIGN: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter...
January 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Fei Li, Bin Liu, Xiaolan Zhou, Quan Xu
DNA damage response induced by ionizing radiation (IR) is an important event that involved in the sensitivity and efficiency of radiotherapy in human medulloblastoma. RNF8 is a E3 ubiquitin ligase and has key roles in the process of DNA damage and repair. Our study aimed to evaluate the effect of RNF8 in the DNA damage repair induced by IR exposure in medulloblastoma cells. We found that the levels of RNF8 were significantly up-regulated by γ-ray irradiation in a dose-dependent manner in medulloblastoma cells, and colocalized with γ-H2AX, a sensitive marker of DNA double strand break induced by γ-ray radiation...
January 10, 2018: Oncology Research
Kaili Zhang, Lei Wang, Haiyan Zhao, Wei Jiang
Transcription factors (TFs) play central roles in the regulation of gene expression by binding with specific DNA sequences. As a potential diagnostic marker, sensitive detection of TFs is essential for pharmacological research development and clinical disease diagnosis. Here, a new fluorescent method based on target binding protection mediated rolling circle amplification (RCA) was developed for TFs detection. A hairpin probe with recognition site for target binding, cleavage site for Nt.BbvCI digestion and two hanging DNA strands with part of G-quadruplex complementary sequences for signal output was designed...
March 1, 2018: Talanta
Jia Shen, Charles Spruck
Epigenetic abnormalities are now realized as important as genetic alterations in contributing to the initiation and progression of cancer. Recent advancements in the cancer epigenetics field have identified extensive alterations of the epigenetic network in human cancers, including histone modifications and DNA methylation. F-box proteins, the substrate receptors of SCF (SKP1-Cullin1-F-box protein) E3 ubiquitin ligases, can directly and indirectly affect the balance of epigenetic regulation. In this brief review, we discuss our current understanding of F-box proteins in cellular epigenetic regulation and how dysregulation of these processes contribute to cancer development...
December 15, 2017: Oncotarget
Christopher M Hickey, Yang Xie, Mark Hochstrasser
Like many transcription factors, the yeast protein MATalpha2 (α2) undergoes rapid proteolysis via the ubiquitin-proteasome system (UPS). At least two ubiquitylation pathways regulate α2 degradation: one pathway utilizes the ubiquitin ligase (E3) Doa10 and the other the heterodimeric E3 Slx5/Slx8. Doa10 is a transmembrane protein of the endoplasmic reticulum/inner nuclear membrane, whereas Slx5/Slx8 localizes to the nucleus and binds DNA nonspecifically. While a single protein can often be ubiquitylated by multiple pathways, the reasons for this 'division of labor' are not well understood...
January 3, 2018: Molecular Biology of the Cell
Kailiang Zhao, Yang Yang, Guang Zhang, Chenfeng Wang, Decai Wang, Mian Wu, Yide Mei
The tumor suppressor p53 plays a prominent role in the protection against cancer. The activity of p53 is mainly controlled by the ubiquitin E3 ligase Mdm2, which targets p53 for proteasomal degradation. However, the regulation of Mdm2 remains not well understood. Here, we show that MARCH7, a RING domain-containing ubiquitin E3 ligase, physically interacts with Mdm2 and is essential for maintaining the stability of Mdm2. MARCH7 catalyzes Lys63-linked polyubiquitination of Mdm2, which impedes Mdm2 autoubiquitination and degradation, thereby leading to the stabilization of Mdm2...
January 2, 2018: EMBO Reports
Miran Rada, Mohammad Althubiti, Akang E Ekpenyong-Akiba, Koon-Guan Lee, Kong Peng Lam, Olga Fedorova, Nickolai A Barlev, Salvador Macip
p53 is a tumour suppressor that is activated in response to various types of stress. It is regulated by a complex pattern of over 50 different post-translational modifications, including ubiquitination by the E3 ligase MDM2, which leads to its proteasomal degradation. We have previously reported that expression of Bruton's Tyrosine Kinase (BTK) induces phosphorylation of p53 at the N-terminus, including Serine 15, and increases its protein levels and activity. The mechanisms involved in this process are not completely understood...
December 5, 2017: Oncotarget
Quanxin Long, Ran Yan, Jieli Hu, Dawei Cai, Bidisha Mitra, Elena S Kim, Alexander Marchetti, Hu Zhang, Soujuan Wang, Yuanjie Liu, Ailong Huang, Haitao Guo
Hepadnavirus covalently closed circular (ccc) DNA is the bona fide viral transcription template, which plays a pivotal role in viral infection and persistence. Upon infection, the non-replicative cccDNA is converted from the incoming and de novo synthesized viral genomic relaxed circular (rc) DNA, presumably through employment of the host cell's DNA repair mechanisms in the nucleus. The conversion of rcDNA into cccDNA requires preparation of the extremities at the nick/gap regions of rcDNA for strand ligation...
December 2017: PLoS Pathogens
Robert J Bauer, Alexander Zhelkovsky, Katharina Bilotti, Laura E Crowell, Thomas C Evans, Larry A McReynolds, Gregory J S Lohman
DNA ligases catalyze the repair of phosphate backbone breaks in DNA, acting with highest activity on breaks in one strand of duplex DNA. Some DNA ligases have also been observed to ligate two DNA fragments with short complementary overhangs or blunt-ended termini. In this study, several wild-type DNA ligases (phage T3, T4, and T7 DNA ligases, Paramecium bursaria chlorella virus 1 (PBCV1) DNA ligase, human DNA ligase 3, and Escherichia coli DNA ligase) were tested for their ability to ligate DNA fragments with several difficult to ligate end structures (blunt-ended termini, 3'- and 5'- single base overhangs, and 5'-two base overhangs)...
2017: PloS One
Hsin-Ling Yang, Chin-Ling Lee, Mallikarjuna Korivi, Jiunn-Wang Liao, Peramaiyan Rajendran, Jia-Jiuan Wu, You-Cheng Hseu
Ultraviolet A (UVA) irradiation is toxic to skin as it penetrates deep into the dermis and damages cellular components through excessive reactive oxygen species (ROS) production, which accelerates photoaging and skin cancer. We evaluated the dermato-protective efficacies of zerumbone (natural sesquiterpene of Zingiber zerumbet) in UVA-irradiated human skin keratinocyte (HaCaT) cells and mouse epidermis. Zerumbone pretreatment (2-10 μM) substantially suppressed UVA (15 J/cm2)-induced HaCaT cell death and lactate dehydrogenase release in a dose-dependent manner...
December 19, 2017: Biochemical Pharmacology
Timothy R L Howes, Annahita Sallmyr, Rhys Brooks, George E Greco, Darin E Jones, Yoshihiro Matsumoto, Alan E Tomkinson
No abstract text is available yet for this article.
December 19, 2017: DNA Repair
Rohini Bose, Kai Sheng, Adel R Moawad, Gurpreet Manku, Cristian O'Flaherty, Teruko Taketo, Martine Culty, Kin Lam Fok, Simon S Wing
Spermatogenesis consists of a series of highly regulated processes that include mitotic proliferation, meiosis and cellular remodeling. Although alterations in gene expression are well known to modulate spermatogenesis, posttranscriptional mechanisms are less well defined. The ubiquitin proteasome system plays a significant role in protein turnover and may be involved in these posttranscriptional mechanisms. We previously identified ubiquitin ligase Huwe1 in the testis and showed that it can ubiquitinate histones...
December 19, 2017: Scientific Reports
Sue Jin Moon, Byong Chang Jeong, Hwa Jin Kim, Joung Eun Lim, Ghee Young Kwon, Jeong Hoon Kim
Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression...
December 18, 2017: Oncogene
Wolfgang Dubiel, Dawadschargal Dubiel, Dieter A Wolf, Michael Naumann
Specificity of the ubiquitin proteasome system is controlled by ubiquitin E3 ligases, including their major representatives, the multisubunit cullin-RING ubiquitin (Ub) ligases (CRLs). More than 200 different CRLs are divided into seven families according to their cullin scaffolding proteins (CUL1-7) around which they are assembled. Research over two decades has revealed that different CRL families are specialized to fulfill specific cellular functions. Whereas many CUL1-based CRLs (CRL1s) ubiquitylate cell cycle regulators, CRL4 complexes often associate with chromatin to control DNA metabolism...
December 14, 2017: Trends in Biochemical Sciences
Nicholas R Pannunzio, Go Watanabe, Michael R Lieber
Nonhomologous DNA end joining (NHEJ) is the predominant DSB repair pathway throughout the cell cycle and accounts for nearly all DSB repair outside of the S and G2 phases.  NHEJ relies on Ku to thread onto DNA termini and thereby improve the affinity of the NHEJ enzymatic components consisting of polymerases (Pol μ and Pol λ), a nuclease (the Artemis·DNA-PKcs complex), and a ligase (XLF·XRCC4·Lig4 complex).  Each of the enzymatic components is distinctive for its versatility in acting on diverse incompatible DNA end configurations coupled with a flexibility in loading order, resulting in many possible junctional outcomes from one DSB...
December 14, 2017: Journal of Biological Chemistry
Pantazis I Theotokis, Louise Usher, Christopher K Kortschak, Ed Schwalbe, Sterghios A Moschos
Low allelic and clonal variability among endogenous RNAi targets has focused mismatch tolerance studies to RNAi-active guide strands. However, the inherent genomic instability of RNA viruses such as hepatitis C virus (HCV) gives rise to quasi-species mutants within discrete clones: this facilitates mismatch tolerance studies from a target perspective. We recently quantified the slicing imprecision of Argonaute 2 using small interfering RNA (siRNA) analogs of the DNA-directed RNAi drug TT-034 and next-generation sequencing of 5' RNA ligase-mediated rapid amplification of cDNA ends (RACE-SEQ)...
December 15, 2017: Molecular Therapy. Nucleic Acids
Daniela Senft, Jianfei Qi, Ze'ev A Ronai
The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes...
December 15, 2017: Nature Reviews. Cancer
Shuo Liu, Minghong Jiang, Wendie Wang, Wei Liu, Xiaoqi Song, Zhongfei Ma, Shikun Zhang, Lun Liu, Yin Liu, Xuetao Cao
Prolonged activation of interferon-STAT1 signaling is closely related to inflammatory autoimmune disorders, and therefore the identification of negative regulators of these pathways is important. Through high-content screening of 115 mouse RING-domain E3 ligases, we identified the E3 ubiquitin ligase RNF2 as a potent inhibitor of interferon-dependent antiviral responses. RNF2 deficiency substantially enhanced interferon-stimulated gene (ISG) expression and antiviral responses. Mechanistically, nuclear RNF2 directly bound to STAT1 after interferon stimulation and increased K33-linked polyubiquitination of the DNA-binding domain of STAT1 at position K379, in addition to promoting the disassociation of STAT1/STAT2 from DNA and consequently suppressing ISG transcription...
January 2018: Nature Immunology
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