scholarly journals PARPs in genome stability and signal transduction: implications for cancer therapy

2018 ◽  
Vol 46 (6) ◽  
pp. 1681-1695 ◽  
Author(s):  
Luca Palazzo ◽  
Ivan Ahel
Keyword(s):  
Signal Transduction ◽  
Dna Damage Response ◽  
Nicotinamide Adenine Dinucleotide ◽  
Genome Stability ◽  
Human Cancer ◽  
Cellular Functions ◽  
Target Proteins ◽  
Cellular Processes ◽  
Damage Response ◽  
Tankyrase 1

The poly(ADP-ribose) polymerase (PARP) superfamily of enzymes catalyses the ADP-ribosylation (ADPr) of target proteins by using nicotinamide adenine dinucleotide (NAD+) as a donor. ADPr reactions occur either in the form of attachment of a single ADP-ribose nucleotide unit on target proteins or in the form of ADP-ribose chains, with the latter called poly(ADP-ribosyl)ation. PARPs regulate many cellular processes, including the maintenance of genome stability and signal transduction. In this review, we focus on the PARP family members that possess the ability to modify proteins by poly(ADP-ribosyl)ation, namely PARP1, PARP2, Tankyrase-1, and Tankyrase-2. Here, we detail the cellular functions of PARP1 and PARP2 in the regulation of DNA damage response and describe the function of Tankyrases in Wnt-mediated signal transduction. Furthermore, we discuss how the understanding of these pathways has provided some major breakthroughs in the treatment of human cancer.

A cohesin–RAD21 interactome

2012 ◽  
Vol 442 (3) ◽  
pp. 661-670 ◽  
Author(s):  
Anil K. Panigrahi ◽  
Nenggang Zhang ◽  
Subhendu K. Otta ◽  
Debananda Pati
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Modification ◽  
Cohesin Complex ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Nuclear Extracts ◽  
Protein Interactome ◽  
Damage Response ◽  
Induced Apoptosis

The cohesin complex holds the sister chromatids together from S-phase until the metaphase-to-anaphase transition, and ensures both their proper cohesion and timely separation. In addition to its canonical function in chromosomal segregation, cohesin has been suggested by several lines of investigation in recent years to play additional roles in apoptosis, DNA-damage response, transcriptional regulation and haematopoiesis. To better understand the basis of the disparate cellular functions of cohesin in these various processes, we have characterized a comprehensive protein interactome of cohesin–RAD21 by using three independent approaches: Y2H (yeast two-hybrid) screening, immunoprecipitation-coupled-MS of cytoplasmic and nuclear extracts from MOLT-4 T-lymphocytes in the presence and absence of etoposide-induced apoptosis, and affinity pull-down assays of chromatographically purified nuclear extracts from pro-apoptotic MOLT-4 cells. Our analyses revealed 112 novel protein interactors of cohesin–RAD21 that function in different cellular processes, including mitosis, regulation of apoptosis, chromosome dynamics, replication, transcription regulation, RNA processing, DNA-damage response, protein modification and degradation, and cytoskeleton and cell motility. Identification of cohesin interactors provides a framework for explaining the various non-canonical functions of the cohesin complex.

scholarly journals The Roles of SPOP in DNA Damage Response and DNA Replication

2020 ◽  
Vol 21 (19) ◽  
pp. 7293
Author(s):  
Masashi Maekawa ◽  
Shigeki Higashiyama
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Substrate Binding ◽  
Critical Role ◽  
Tumor Formation ◽  
Missense Mutations ◽  
Cellular Functions ◽  
Damage Response

Speckle-type BTB/POZ protein (SPOP) is a substrate recognition receptor of the cullin-3 (CUL3)/RING type ubiquitin E3 complex. To date, approximately 30 proteins have been identified as ubiquitinated substrates of the CUL3/SPOP complex. Pathologically, missense mutations in the substrate-binding domain of SPOP have been found in prostate and endometrial cancers. Prostate and endometrial cancer-associated SPOP mutations lose and increase substrate-binding ability, respectively. Expression of these SPOP mutants, thus, causes aberrant turnovers of the substrate proteins, leading to tumor formation. Although the molecular properties of SPOP and its cancer-associated mutants have been intensively elucidated, their cellular functions remain unclear. Recently, a number of studies have uncovered the critical role of SPOP and its mutants in DNA damage response and DNA replication. In this review article, we summarize the physiological functions of SPOP as a “gatekeeper” of genome stability.

scholarly journals The PARP Way to Epigenetic Changes

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 446
Author(s):  
Simone Ummarino ◽  
Clinton Hausman ◽  
Annalisa Di Ruscio
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Nicotinamide Adenine Dinucleotide ◽  
Epigenetic Changes ◽  
Biological Functions ◽  
Post Translational Modification ◽  
Therapeutic Implications ◽  
Cellular Processes ◽  
Damage Response

ADP-ribosylation, is a reversible post-translational modification implicated in major biological functions. Poly ADP-ribose polymerases (PARP) are specialized enzymes that catalyze the addition of ADP ribose units from “nicotinamide adenine dinucleotide-donor molecules” to their target substrates. This reaction known as PARylation modulates essential cellular processes including DNA damage response, chromatin remodeling, DNA methylation and gene expression. Herein, we discuss emerging roles of PARP1 in chromatin remodeling and epigenetic regulation, focusing on its therapeutic implications for cancer treatment and beyond.

WDNfinder: A method for minimum driver node set detection and analysis in directed and weighted biological network

2017 ◽  
Vol 15 (05) ◽  
pp. 1750021 ◽  
Author(s):  
Yanshuo Chu ◽  
Zhenxing Wang ◽  
Rongjie Wang ◽  
Ningyi Zhang ◽  
Jie Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Biological Networks ◽  
Domain Knowledge ◽  
Human Cancer ◽  
Accurate Analysis ◽  
Response Network ◽  
Public Data ◽  
Damage Response ◽  
Structural Controllability

Structural controllability is the generalization of traditional controllability for dynamical systems. During the last decade, interesting biological discoveries have been inferred by applied structural controllability analysis to biological networks. However, false positive/negative information (i.e. nodes and edges) widely exists in biological networks that documented in public data sources, which can hinder accurate analysis of structural controllability. In this study, we propose WDNfinder, a comprehensive analysis package that provides structural controllability with consideration of node connection strength in biological networks. When applied to the human cancer signaling network and p53-mediate DNA damage response network, WDNfinder shows high accuracy on essential nodes prediction in these networks. Compared to existing methods, WDNfinder can significantly narrow down the set of minimum driver node set (MDS) under the restriction of domain knowledge. When using p53-mediate DNA damage response network as illustration, we find more meaningful MDSs by WDNfinder. The source code is implemented in python and publicly available together with relevant data on GitHub: https://github.com/dustincys/WDNfinder .

scholarly journals Author Correction: ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Jung-Hee Lee ◽  
Seon-Joo Park ◽  
Gurusamy Hariharasudhan ◽  
Min-Ji Kim ◽  
Sung Mi Jung ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Damage Response ◽  
Maintain Genome Stability

scholarly journals Guanine Quadruplex DNA Regulates Gamma Radiation Response of Genome Functions in the Radioresistant Bacterium Deinococcus radiodurans

2019 ◽  
Vol 201 (17) ◽  
Author(s):  
Shruti Mishra ◽  
Reema Chaudhary ◽  
Sudhir Singh ◽  
Swathi Kota ◽  
Hari S. Misra
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Deinococcus Radiodurans ◽  
Dna Structure ◽  
Protein Translation ◽  
Content Type ◽  
Cellular Processes ◽  
G4 Dna ◽  
Guanine Quadruplex ◽  
Damage Response

ABSTRACT Guanine quadruplex (G4) DNA/RNA are secondary structures that regulate the various cellular processes in both eukaryotes and bacteria. Deinococcus radiodurans, a Gram-positive bacterium known for its extraordinary radioresistance, shows a genomewide occurrence of putative G4 DNA-forming motifs in its GC-rich genome. N-Methyl mesoporphyrin (NMM), a G4 DNA structure-stabilizing drug, did not affect bacterial growth under normal conditions but inhibited the postirradiation recovery of gamma-irradiated cells. Transcriptome sequencing analysis of cells treated with both radiation and NMM showed repression of gamma radiation-responsive gene expression, which was observed in the absence of NMM. Notably, this effect of NMM on the expression of housekeeping genes involved in other cellular processes was not observed. Stabilization of G4 DNA structures mapped at the upstream of recA and in the encoding region of DR_2199 had negatively affected promoter activity in vivo, DNA synthesis in vitro and protein translation in Escherichia coli host. These results suggested that G4 DNA plays an important role in DNA damage response and in the regulation of expression of the DNA repair proteins required for radioresistance in D. radiodurans. IMPORTANCE Deinococcus radiodurans can recover from extensive DNA damage caused by many genotoxic agents. It lacks LexA/RecA-mediated canonical SOS response. Therefore, the molecular mechanisms underlying the regulation of DNA damage response would be worth investigating in this bacterium. D. radiodurans genome is GC-rich and contains numerous islands of putative guanine quadruplex (G4) DNA structure-forming motifs. Here, we showed that in vivo stabilization of G4 DNA structures can impair DNA damage response processes in D. radiodurans. Essential cellular processes such as transcription, DNA synthesis, and protein translation, which are also an integral part of the double-strand DNA break repair pathway, are affected by the arrest of G4 DNA structure dynamics. Thus, the role of DNA secondary structures in DNA damage response and radioresistance is demonstrated.

scholarly journals Virus DNA Replication and the Host DNA Damage Response

2018 ◽  
Vol 5 (1) ◽  
pp. 141-164 ◽  
Author(s):  
Matthew D. Weitzman ◽  
Amélie Fradet-Turcotte
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Life Cycles ◽  
Dynamic Interactions ◽  
Dna Damage And Repair ◽  
Dna Viruses ◽  
Cellular Processes ◽  
Damage Response ◽  
Cellular Replication ◽  
Cellular Dna

Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their genomes and generate progeny virions. Studies of viruses and how they interact with cellular processes have historically provided seminal insights into basic biology and disease mechanisms. The replicative life cycles of many DNA viruses have been shown to engage components of the host DNA damage and repair machinery. Viruses have evolved numerous strategies to navigate the cellular DNA damage response. By hijacking and manipulating cellular replication and repair processes, DNA viruses can selectively harness or abrogate distinct components of the cellular machinery to complete their life cycles. Here, we highlight consequences for viral replication and host genome integrity during the dynamic interactions between virus and host.

scholarly journals TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

2016 ◽  
Vol 212 (3) ◽  
pp. 281-288 ◽  
Author(s):  
Pavel Moudry ◽  
Kenji Watanabe ◽  
Kamila M. Wolanin ◽  
Jirina Bartkova ◽  
Isabel E. Wassing ◽  
...  
Keyword(s):  
Dna Damage Response ◽  
Small Interfering Rna ◽  
Human Cancer ◽  
Parp Inhibitor ◽  
Clinical Implications ◽  
Ovarian Carcinomas ◽  
Damage Response ◽  
Dna End Resection ◽  
Interfering Rna ◽  
End Resection

Topoisomerase IIβ-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. TOPBP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase–mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. Overall, our results provide mechanistic insights into TOPBP1’s role in HR, with potential clinical implications for cancer treatment.

scholarly journals Endonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wenjun Wang ◽  
Jianshuang Li ◽  
Junyang Tan ◽  
Miaomiao Wang ◽  
Jing Yang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Glycogen Synthase ◽  
Endonuclease Activity ◽  
Phosphatidylinositol 3 Kinase ◽  
Endonuclease G ◽  
C Elegans ◽  
Cellular Processes ◽  
Damage Response ◽  
Type 3

AbstractEndonuclease G (ENDOG), a mitochondrial nuclease, is known to participate in many cellular processes, including apoptosis and paternal mitochondrial elimination, while its role in autophagy remains unclear. Here, we report that ENDOG released from mitochondria promotes autophagy during starvation, which we find to be evolutionally conserved across species by performing experiments in human cell lines, mice, Drosophila and C. elegans. Under starvation, Glycogen synthase kinase 3 beta-mediated phosphorylation of ENDOG at Thr-128 and Ser-288 enhances its interaction with 14-3-3γ, which leads to the release of Tuberin (TSC2) and Phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34) from 14-3-3γ, followed by mTOR pathway suppression and autophagy initiation. Alternatively, ENDOG activates DNA damage response and triggers autophagy through its endonuclease activity. Our results demonstrate that ENDOG is a crucial regulator of autophagy, manifested by phosphorylation-mediated interaction with 14-3-3γ, and its endonuclease activity-mediated DNA damage response.

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