Involvement of Matrin 3 and SFPQ/NONO in the DNA damage response

Salton, Maayan; Lerenthal, Yaniv; Wang, Shih Ya; Chen, David J.; Shiloh, Yosef

doi:10.4161/cc.9.8.11298

Cited by 190 publications

(191 citation statements)

References 73 publications

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“…Since then, diverse studies have described it as a protein with pleiotropic functions mainly involved in RNA processing and transport, as well as a transcription factor (27). It has been implicated in diverse pathways, such as nuclear receptor signaling (35), DNA repair (36,37), and viral infection (38). Here we have shown that it can directly activate the p16-Ink4A locus, an important regulator of the G1 exit checkpoint of the cell cycle.…”

Section: Discussionmentioning

confidence: 69%

NONO couples the circadian clock to the cell cycle

Kowalska

Ripperger

Hoegger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

222

210

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Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PE-RIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER proteindependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.keratinocyte | p54nrb | RNA-binding protein | paraspeckle protein T he circadian clock adapts organisms to their daily surroundings both behaviorally and physiologically. In animals, not only are complex behaviors such as sleep and mood governed by this oscillator, but also different body functions such as digestion, circulation, and respiration (1). The basic mechanism of this clock is cell-autonomous in all studied species possessing a circadian clock. In mammals, individual clocks in most cells are synchronized by a brain "master clock" in the suprachiasmatic nucleus of the hypothalamus to orchestrate all rhythmic physiology (2). On a cellular level, circadian physiology extends even to processes such as proliferation (3-7), apoptosis (8), and DNA damage repair (6, 9), which are thought to play important roles in cancer control (8,10).In individual cells, the circadian clock mechanism consists of oscillating feedback loops of transcription of "core" oscillator genes and posttranslational modifications of their protein products that regulate protein stability, activity, and/or localization. For example, in mammals the transcription of periods (Per) and cryptochomes (Cry) are activated by BMAL1:CLOCK heterodimers at cisacting elements called E-boxes, and their protein products form complexes that repress their own transcription (11). We originally identified the RNA-binding protein NONO (also called p54nrb) biochemically as a new member of this circadian transcriptional repressor complex in mice, and mutation of its ortholog NonA in flies resulted in severe attenuation of circadian rhythmicity (12). However, apart from its interaction with this circadian repressor complex, NONO's mechanism of action within the clock remains unknown.The mechanism of the cell cycle has been reviewed extensively elsewhere (13,14). Rathe...

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Section: Discussionmentioning

confidence: 69%

NONO couples the circadian clock to the cell cycle

Kowalska

Ripperger

Hoegger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

222

210

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“…Whether this reflects inhibition of RNA pol I function or engagement of the paraspeckle proteins in other nucleolus-associated activities in the nucleolar domain is not presently known. p54NRB/NONO has also recently been associated with DNA double-strand break repair and damage recovery (64,65).…”

Section: Ir Induces Fast and Transient Changes Of Nucleolar Pro-mentioning

confidence: 99%

Quantitative Proteomics and Dynamic Imaging of the Nucleolus Reveal Distinct Responses to UV and Ionizing Radiation

Moore

Bai

Boisvert

et al. 2011

Molecular & Cellular Proteomics

120

113

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The nucleolus is a nuclear organelle that coordinates rRNA transcription and ribosome subunit biogenesis. Recent proteomic analyses have shown that the nucleolus contains proteins involved in cell cycle control, DNA processing and DNA damage response and repair, in addition to the many proteins connected with ribosome subunit production. Here we study the dynamics of nucleolar protein responses in cells exposed to stress and DNA damage caused by ionizing and ultraviolet (UV) radiation in diploid human fibroblasts. We show using a combination of imaging and quantitative proteomics methods that nucleolar substructure and the nucleolar proteome undergo selective reorganization in response to UV damage. The proteomic responses to UV include alterations of functional protein complexes such as the SSU processome and exosome, and paraspeckle proteins, involving both decreases and increases in steady state protein ratios, respectively. Several nonhomologous end-joining proteins (NHEJ), such as Ku70/80, display similar fast responses to UV. In contrast, nucleolar proteomic responses to IR are both temporally and spatially distinct from those caused by UV, and more limited in terms of magnitude. With the exception of the NHEJ and paraspeckle proteins, where IR induces rapid and transient changes within 15 min of the damage, IR does not alter the ratios of most other functional nucleolar protein complexes. The rapid transient decrease of NHEJ proteins in the nucleolus indicates that it may reflect a response to DNA damage. Our results underline that the nucleolus is a specific stress response organelle that responds to different damage and stress agents in a unique, damagespecific manner.

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“…3B) (54,55) Also, the IRES-enriched factor DEK is known to associate with both exon junction complexes as well as nucleosomes and as the STRING network indicates, it could be a central linking factor that bridges chromatin and mRNA processing (56). Finally, a second IRES-enriched subgroup is notable in that two of the three known components of paraspeckles were consistently enriched with tagged-IRES purification (MATR3 and SFPQ) (39,57,58). The third protein component of paraspeckles, NONO/p54nrb, was enriched in only one dataset (57), Paraspeckles are nuclear bodies built upon the NEAT1 noncoding RNA and they appear to function…”

Section: Validation Of Selected Ires Bindingmentioning

confidence: 99%

Quantitative Profiling of In Vivo-assembled RNA-Protein Complexes Using a Novel Integrated Proteomic Approach

Tsai

Wang

Huang

et al. 2011

Molecular & Cellular Proteomics

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-1, eIF-2A, and eIF3g), and ribosomal subunits with known noncanonical actions (RPS19, RPS7, and RPL26). Validation studies with the small molecule eIF4A-1 inhibitor Hippuristanol shows that translation of endogenous lymphoid enhancer factor-1 mRNA is especially sensitive to eIF4A-1 activity. Our work demonstrates that MS2 in vivo biotin tagged RNA affinity purification is an effective and versatile approach

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Involvement of Matrin 3 and SFPQ/NONO in the DNA damage response

Cited by 190 publications

References 73 publications

NONO couples the circadian clock to the cell cycle

NONO couples the circadian clock to the cell cycle

Quantitative Proteomics and Dynamic Imaging of the Nucleolus Reveal Distinct Responses to UV and Ionizing Radiation

Quantitative Profiling of In Vivo-assembled RNA-Protein Complexes Using a Novel Integrated Proteomic Approach

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