MORC2 Signaling Integrates Phosphorylation-Dependent, ATPase-Coupled Chromatin Remodeling during the DNA Damage Response

Li, Da‐Qiang; Nair, Sujit S.; Ohshiro, Kazufumi; Kumar, Anupam; Nair, Vasudha S.; Pakala, Suresh B.; Reddy, Sirigiri Divijendra Natha; Gajula, Rajendra P.; Eswaran, Jeyanthy; Aravind, L.; Kumar, Rakesh

doi:10.1016/j.celrep.2012.11.018

Cited by 122 publications

(179 citation statements)

References 49 publications

(66 reference statements)

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“…Their nucleosome-remodeling activity at damage sites is triggered by PAK1-dependent phosphorylation, resulting in a subsequent decondensation of chromatin that provides accessibility to the lesion (Li et al, 2012a). Although MORC orthologs are present in Arabidopsis, their only described role is to establish heterochromatin regions (Lorkovi c, 2012;Moissiard et al, 2012).…”

Section: Chromatin-remodeling Complexes Connected With Ddrmentioning

confidence: 99%

DNA Damage Repair in the Context of Plant Chromatin

Donà

Scheid

2015

Plant Physiol.

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The integrity of DNA molecules is constantly challenged. All organisms have developed mechanisms to detect and repair multiple types of DNA lesions. The basic principles of DNA damage repair (DDR) in prokaryotes and unicellular and multicellular eukaryotes are similar, but the association of DNA with nucleosomes in eukaryotic chromatin requires mechanisms that allow access of repair enzymes to the lesions. This is achieved by chromatin-remodeling factors, and their necessity for efficient DDR has recently been demonstrated for several organisms and repair pathways. Plants share many features of chromatin organization and DNA repair with fungi and animals, but they differ in other, important details, which are both interesting and relevant for our understanding of genome stability and genetic diversity. In this Update, we compare the knowledge of the role of chromatin and chromatin-modifying factors during DDR in plants with equivalent systems in yeast and humans. We emphasize plant-specific elements and discuss possible implications.A DNA molecule in a eukaryotic chromosome has a diameter of 2 nm but a length in the range of centimeters. Being 10 7 times longer than it is wide would make it highly sensitive to breakage if it were not organized in compact and dynamic chromatin, with nucleosomes as basic units followed by multiple higher order levels of organization. Within this packaging, replication and transcription constitute an endogenous mechanical strain, while exposure of cells to physical or chemical hazard creates a wide range of DNA damage induced by external factors, including photoproducts, pyrimidine dimers, interstrand crosslinking, and single and double-strand breaks (DSBs). All organisms possess mechanisms that repair DNA molecules. DNA damage repair (DDR) systems for the various types of damage are overlapping as well as complementary, and their prevalence depends on the organism, the stage of the cell cycle, the site and the amount of damage, and the availability of intact templates. A coarse categorization distinguishes nucleotide excision repair, base excision repair, nonhomologous end joining (NHEJ), and homologous recombination (HR). Many schematic models for these DDR pathways describe the action and interaction of several repair components, but they are usually misleading in one aspect: DNA strands are illustrated as straight lines, neglecting the emerging role of chromatin for the location and the fate of DNA lesions. More realistically, we should envisage DNA lesions in the chromatin context like the leakage or burst of an in-ground pipe. Recognizing the defect, localizing it, excavating the broken parts, cleaning the ends, reconnecting them, and restoring the original state are mirrored in the subsequent steps of DDR: signaling, labeling, accessing, resecting, religating, and reassembling. Chromatin is expected to especially affect the access, resection, and restoration of the original arrangement, and several factors that can dissolve higher order structures, slide, evict, or exchange ...

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Section: Chromatin-remodeling Complexes Connected With Ddrmentioning

confidence: 99%

DNA Damage Repair in the Context of Plant Chromatin

Donà

Scheid

2015

Plant Physiol.

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“…Since MORC3 was recruited to HSV-1 genomes, directly interacts with PML.I, and in one situation is required for Sp100 localizing to PML NBs (12, 13), we investigated whether MORC3 influences the recruitment of these other factors to HSV-1 genomes. In addition, another MORC family protein, MORC2, has been reported to induce phosphorylation of H2AX and the subsequent formation of ␥H2AX foci and chromatin relaxation (20), which are steps in the pathway to double-strand break repair (80). Because it has been established that ␥H2AX forms regions surrounding replicating HSV-1 genomes in a double-strand break repair response (81-83), we included ␥H2AX in our panel of proteins to investigate whether their recruitment was influenced by MORC3.…”

Section: Morc3 Colocalizes With Icp0 Prior To Its Degradation Morc3mentioning

confidence: 99%

“…There are three conserved domains within MORC3: the GHL (gyrase B, Hsp90, and MutL) ATPase domain (14), a CW-type zinc finger domain (15), and a coiled-coil dimerization domain (16,17). The GHL-ATPase domain is thought to be involved in gene silencing and regulation of chromatin structure in response to DNA damage signals (18)(19)(20) and is required for localization of MORC3 to PML NBs and the recruitment of Sp100 and p53 to these structures (12). The CW-type zinc finger domain contains a histone H3 binding motif which binds predominantly methylated lysine 4 of histone H3 (21)(22)(23).…”

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confidence: 99%

MORC3, a Component of PML Nuclear Bodies, Has a Role in Restricting Herpes Simplex Virus 1 and Human Cytomegalovirus

Sloan

Orr

Everett

2016

J Virol

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We previously reported that MORC3, a protein associated with promyelocytic leukemia nuclear bodies (PML NBs), is a target of herpes simplex virus 1 (HSV-1) ICP0-mediated degradation (E. Sloan, et al., PLoS Pathog 11:e1005059, 2015, http: //dx.doi.org/10.1371/journal.ppat.1005059). Since it is well known that certain other components of the PML NB complex play an important role during an intrinsic immune response to HSV-1 and are also degraded or inactivated by ICP0, here we further investigate the role of MORC3 during HSV-1 infection. We demonstrate that MORC3 has antiviral activity during HSV-1 infection and that this antiviral role is counteracted by ICP0. In addition, MORC3's antiviral role extends to wild-type (wt) human cytomegalovirus (HCMV) infection, as its plaque-forming efficiency increased in MORC3-depleted cells. We found that MORC3 is recruited to sites associated with HSV-1 genomes after their entry into the nucleus of an infected cell, and in wt infections this is followed by its association with ICP0 foci prior to its degradation. The RING finger domain of ICP0 was required for degradation of MORC3, and we confirmed that no other HSV-1 protein is required for the loss of MORC3. We also found that MORC3 is required for fully efficient recruitment of PML, Sp100, hDaxx, and ␥H2AX to sites associated with HSV-1 genomes entering the host cell nucleus. This study further unravels the intricate ways in which HSV-1 has evolved to counteract the host immune response and reveals a novel function for MORC3 during the host intrinsic immune response. IMPORTANCEHerpesviruses have devised ways to manipulate the host intrinsic immune response to promote their own survival and persistence within the human population. One way in which this is achieved is through degradation or functional inactivation of PML NB proteins, which are recruited to viral genomes in order to repress viral transcription. Because MORC3 associates with PML NBs in uninfected cells and is a target for HSV-1-mediated degradation, we investigated the role of MORC3 during HSV-1 infection. We found that MORC3 is also recruited to viral HSV-1 genomes, and importantly it contributes to the fully efficient recruitment of PML, hDaxx, Sp100, and ␥H2AX to these sites. Depletion of MORC3 resulted in an increase in ICP0-null HSV-1 and wt HCMV replication and plaque formation; therefore, this study reveals that MORC3 is an antiviral factor which plays an important role during HSV-1 and HCMV infection. Herpes simplex virus 1 (HSV-1) is prevalent in populations throughout the world and is responsible for a number of clinically important diseases that range from facial and genital lesions to encephalitis (1, 2). This alphaherpesvirus establishes lifelong persistence within the host, remaining latent within sensory ganglia after the primary infection is resolved. Periodically the virus is reactivated from its latent state, resulting in recurrent lesions. HSV-1 has the capacity to remain persistent within the host and allow transmission within the popu...

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“…The transfection of siRNA was performed twice at 24-h intervals with Oligofectamine reagent (Invitrogen) following the manufacturer's protocol. Cells were subjected to further analyses after 48 h of the second transfection 57 .…”

Section: Methodsmentioning

confidence: 99%

“…Plasmid DNA was purified using QIAGEN Plasmid Midi Kit (QIAGEN, Valencia, CA) and transfections were carried out using FuGENE HD Transfection Reagent (Roche Applied Science, Indianapolis, IN) according to the manufacturer's instructions. Cells were co-transfected with the indicated vectors, and the total amount of DNA was maintained equal with corresponding empty vectors 57 . The transfection of siRNA was performed twice at 24-h intervals with Oligofectamine reagent (Invitrogen) following the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Metastasis-associated protein 1 is an integral component of the circadian molecular machinery

Pakala

Reddy

et al. 2013

Nat Commun

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The mammalian circadian clock regulates the daily cycles of many important physiological processes, but its mechanism is not well understood. Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. Knockout of MTA1 in mice disrupts the free-running period of circadian rhythms under constant light and normal entrainment of behaviour to 12-h-light/12-h-dark cycles. The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. Moreover, MTA1 deacetylates BMAL1 at lysine 538 through regulating deacetylase SIRT1 expression, thus disturbing the CRY1-mediated negative feedback loop. These findings uncover a previously unappreciated role for MTA1 in maintenance of circadian rhythmicity through acting on the positive limb of the clock machinery.

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MORC2 Signaling Integrates Phosphorylation-Dependent, ATPase-Coupled Chromatin Remodeling during the DNA Damage Response

Cited by 122 publications

References 49 publications

DNA Damage Repair in the Context of Plant Chromatin

DNA Damage Repair in the Context of Plant Chromatin

MORC3, a Component of PML Nuclear Bodies, Has a Role in Restricting Herpes Simplex Virus 1 and Human Cytomegalovirus

Metastasis-associated protein 1 is an integral component of the circadian molecular machinery

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