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 ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. VOLUME 283 (2008) PAGES 6572-6583

2008 ◽  
Vol 283 (22) ◽  
pp. 15512
Author(s):  
Navjotsingh Pabla ◽  
Shuang Huang ◽  
Qing-Sheng Mi ◽  
Rene Daniel ◽  
Zheng Dong
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response ◽  
P53 Activation ◽  
Induced Apoptosis

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 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.

scholarly journals Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity

2018 ◽  
Vol 315 (3) ◽  
pp. F469-F478 ◽  
Author(s):  
Liping Sun ◽  
Jing Liu ◽  
Yanggang Yuan ◽  
Xinzhou Zhang ◽  
Zheng Dong
Keyword(s):  
Dna Damage ◽  
Histone Acetylation ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
The Body ◽  
Heme Oxygenase 1 ◽  
Antioxidant Genes ◽  
Cisplatin Nephrotoxicity ◽  
Damage Response ◽  
Induced Apoptosis

As a potent chemotherapy drug, cisplatin is also notorious for its side-effects including nephrotoxicity in kidneys, presenting a pressing need to identify renoprotective agents. Cisplatin nephrotoxicity involves epigenetic regulations, including changes in histone acetylation. Bromodomain and extraterminal (BET) proteins are “readers” of the epigenetic code of histone acetylation. Here, we investigated the potential renoprotective effects of JQ1, a small molecule inhibitor of BET proteins. We show that JQ1 significantly ameliorated cisplatin-induced nephrotoxicity in mice as indicated by the measurements of kidney function, histopathology, and renal tubular apoptosis. JQ1 also partially prevented the body weight loss during cisplatin treatment in mice. Consistently, JQ1 inhibited cisplatin-induced apoptosis in renal proximal tubular cells. Mechanistically, JQ1 suppressed cisplatin-induced phosphorylation or activation of p53 and Chk2, key events in DNA damage response. JQ1 also attenuated cisplatin-induced MAP kinase (p38, ERK1/2, and JNK) activation. In addition, JQ1 enhanced the expression of antioxidant genes including nuclear factor erythroid 2-related factor 2 and heme oxygenase-1, while diminishing the expression of the nitrosative protein inducible nitric oxide synthase. JQ1 did not suppress cisplatin-induced apoptosis in A549 nonsmall cell lung cancer cells and AGS gastric cancer cells. These results suggest that JQ1 may protect against cisplatin nephrotoxicity by suppressing DNA damage response, p53, MAP kinases, and oxidative/nitrosative stress pathways.

Recent Advances in Therapeutic Application of DNA Damage Response Inhibitors against Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Stina George Fernandes ◽  
Prachi Shah ◽  
Ekta Khattar
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Dna Integrity ◽  
Normal Cells ◽  
Cellular Processes ◽  
Damage Response ◽  
Environmental Agents ◽  
Genomic Damage ◽  
Sensor Proteins

: DNA integrity is continuously challenged by intrinsic cellular processes and environmental agents. To overcome this genomic damage, cells have developed multiple signaling pathways collectively named as DNA damage response (DDR) and composed of three components: (i) sensor proteins, which detect DNA damage, (ii) mediators that relay the signal downstream and recruit the repair machinery, and (iii) the repair proteins, which restore the damaged DNA. A flawed DDR and failure to repair the damage lead to the accumulation of genetic lesions and increased genomic instability, which is recognized as a hallmark of cancer. Cancer cells tend to harbor increased mutations in DDR genes and often have fewer DDR pathways than normal cells. This makes cancer cells more dependent on particular DDR pathways and thus become more susceptible to compounds inhibiting those pathways compared to normal cells, which have all the DDR pathways intact. Understanding the roles of different DDR proteins in the DNA damage response and repair pathways and identification of their structures have paved the way for the development of their inhibitors as targeted cancer therapy. In this review, we describe the major participants of various DDR pathways, their significance in carcinogenesis, and focus on the inhibitors developed against several key DDR proteins.

scholarly journals Mammalian PER2 regulates AKT activation and DNA damage response

2012 ◽  
Vol 90 (6) ◽  
pp. 675-682 ◽  
Author(s):  
Xiaoming Yang ◽  
Xuezhong He ◽  
Zhengguan Yang ◽  
Esmaiel Jabbari
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Down Regulation ◽  
Akt Activation ◽  
Cycle Arrest ◽  
Damage Response ◽  
Induced Apoptosis ◽  
Tumor Suppressive Function ◽  
Clock Protein

PER2 is a key mammalian circadian clock protein. It also has a tumor suppressive function. Down regulation of PER2 in the cultured cancer cells accelerates cell proliferation, while overexpression of PER2 inhibits cell growth and induces apoptosis. The Per2 mutant mice have a cancer prone phenotype and an altered DNA damage response. Here we report that PER2 regulates AKT activity. Cells with down-regulated PER2 expression have prolonged high levels of AKT T308 phosphorylation after growth factor stimulation or DNA damage. PER2 down-regulation delays DNA damage induced Chk2 activation and overrides DNA damage induced apoptosis and cell cycle arrest.

scholarly journals ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 845
Author(s):  
Liem Minh Phan ◽  
Abdol-Hossein Rezaeian
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Signaling Pathways ◽  
Dna Damage Response ◽  
Cancer Development ◽  
Cellular Processes ◽  
Cycle Arrest ◽  
Damage Response ◽  
Cancer Cell Survival

ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development.

scholarly journals Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Johannes Gregor Matthias Rack ◽  
Qiang Liu ◽  
Valentina Zorzini ◽  
Jim Voorneveld ◽  
Antonio Ariza ◽  
...  
Keyword(s):  
Dna Damage ◽  
Structural Analysis ◽  
Dna Damage Response ◽  
Posttranslational Modification ◽  
Molecular Basis ◽  
Branched Polymers ◽  
Coordination Geometry ◽  
Cellular Processes ◽  
Damage Response ◽  
Hydrolysis Of

AbstractPoly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromatin structure and Wnt signalling. Despite decades of research, the principles and mechanisms underlying all steps of PAR removal remain actively studied. In this work, we synthesise well-defined PAR branch point molecules and demonstrate that PARG, but not ARH3, can resolve this distinct PAR architecture. Structural analysis of ARH3 in complex with dimeric ADP-ribose as well as an ADP-ribosylated peptide reveal the molecular basis for the hydrolysis of linear and terminal ADP-ribose linkages. We find that ARH3-dependent hydrolysis requires both rearrangement of a catalytic glutamate and induction of an unusual, square-pyramidal magnesium coordination geometry.

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