Chromatin Modifications Associated with DNA Double-strand Breaks Repair as Potential Targets for Neurological Diseases

Brochier, Camille; Langley, Brett

doi:10.1007/s13311-013-0210-9

Cited by 29 publications

(21 citation statements)

References 118 publications

(138 reference statements)

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“…To our knowledge, the prospect that exposure of neurons to growth inhibitory molecules-such as MAG, Nogo-A, or CSPGs-induces DNA damage or genomic instability has not been reported. To determine whether DNA damage occurs downstream of growth inhibition signaling, we measured the accumulation of phosphorylated histone H2AX, an early marker of DNA breaks (30). Neurons were exposed to MAG, Nogo-A, CSPGs, or the DNA-damaging agent camptothecin (CPT), which was used as a positive control (30,31).…”

Section: Parp Is Activated In Cortical Neurons Exposed To Mag Nogo-amentioning

confidence: 99%

“…To determine whether DNA damage occurs downstream of growth inhibition signaling, we measured the accumulation of phosphorylated histone H2AX, an early marker of DNA breaks (30). Neurons were exposed to MAG, Nogo-A, CSPGs, or the DNA-damaging agent camptothecin (CPT), which was used as a positive control (30,31). Unlike CPT, none of the growth-inhibitory molecules induced detectable amounts of H2AX phosphorylation, indicating that PARP1 is activated through a different mechanism (Fig.…”

Section: Parp Is Activated In Cortical Neurons Exposed To Mag Nogo-amentioning

confidence: 99%

“…PARP1 modifies and regulates a variety of nuclear proteins involved in gene regulation, including core histones H2B, H3, and H4, and transcription factors (30,33). As such, we hypothesized that a potential consequence of PARP1 activation in response to inhibitory cues could be the direct PARylation of histones and the transcriptional repression of genes important for axonal regeneration.…”

Section: Parp Inhibition-induced Neurite Outgrowth Does Not Correlatementioning

confidence: 99%

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Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

Brochier

Jones

Willis

et al. 2015

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

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Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules-such as myelin-derived Nogo and myelin-associated glycoprotein-or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration.poly(ADP-ribose) polymerase | PARP1 | PAR | axon | regeneration

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Section: Parp Is Activated In Cortical Neurons Exposed To Mag Nogo-amentioning

confidence: 99%

Section: Parp Is Activated In Cortical Neurons Exposed To Mag Nogo-amentioning

confidence: 99%

Section: Parp Inhibition-induced Neurite Outgrowth Does Not Correlatementioning

confidence: 99%

See 1 more Smart Citation

Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

Brochier

Jones

Willis

et al. 2015

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

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“…11,12 However, to our knowledge, there has been no direct report concerning the role of NRAGE in DDR.…”

Section: (3) Nrage Knockoutmentioning

confidence: 99%

NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8–BARD1 to promote cell survival in squamous esophageal tumorigenesis

Yang

Pan

et al. 2016

Cell Death Differ

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NRAGE, a neurotrophin receptor-interacting melanoma antigen-encoding gene homolog, is significantly increased in the nucleus of radioresistant esophageal tumor cell lines and is highly upregulated to promote cell proliferation in esophageal carcinomas (ECs). However, whether the overexpressed NRAGE promotes cell growth by participating in DNA-damage response (DDR) is still unclear. Here we show that NRAGE is required for efficient double-strand breaks (DSBs) repair via homologous recombination repair (HRR) and downregulation of NRAGE greatly sensitizes EC cells to DNA-damaging agents both in vitro and in vivo. Moreover, NRAGE not only regulates the stability of DDR factors, RNF8 and BARD1, in a ubiquitin-proteolytic pathway, but also chaperons the interaction between BARD1 and RNF8 via their RING domains to form a novel ternary complex. Additionally, the expression of NRAGE is closely correlated with RNF8 and BARD1 in esophageal tumor tissues. In summary, our findings reveal a novel function of NRAGE that will help to guide personalized esophageal cancer treatments by targeting NRAGE to increase cell sensitivity to DNA-damaging therapeutics in the long run. In mammalian cells, DNA lesions are always endogenously and exogenously induced, 1 among which double-strand breaks (DSBs) are the most lethal lesions.2 Therefore, efficient DNA-damage response (DDR) is essential to maintain genomic integrity.1,3 However, DDR is a double-edged sword. In normal organisms, DDR protects cells from tumorigenesis, whereas in tumor cells, DDR enables cells to grow and resist DNA-damaging therapeutic agents. 4 Thus, in order to correctly use DDR factors in cancer diagnosis and targeted therapy, it is important to study molecular pathways underlying DDR in cancer cells. 5NRAGE is a member of the melanoma-associated antigen (MAGE) family. 6 Previous studies reveal that it is possibly a DDR factor: (1) upregulation of NRAGE in the nucleus is highly associated with the development of esophageal carcinoma (EC) by interacting with the proliferating cell nuclear antigen (PCNA); 7 (2) the level of NRAGE is significantly increased in the nucleus of radioresistant EC cells; 8 (3) NRAGE knockout (KO) mice exhibit depression-like behavior 9 and disorder in circadian clock, 10 both of which are analogous to DDR defective scenarios.11,12 However, to our knowledge, there has been no direct report concerning the role of NRAGE in DDR.In the present study, we aim to study the role and the underlying mechanisms of NRAGE in DDR. Our data support that NRAGE is a positive regulator in homologous recombination (HR) and regulates the chemoresistance of EC cells both in vivo and in vitro. From mechanism, it regulates the stability of RNF8 and BARD1 via the ubiquitin-proteasome pathway and interacts with the RING domains of the two proteins as a chaperon to form a novel ternary complex to participate in DDR. Furthermore, clinical characterization of NRAGE, RNF8, and BARD1 in squamous EC tissues shows that the expression of NRAGE protein is closely related wi...

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“…As elegantly summarized by Brochier and Langley (p. XX) [27], DNA damage participates in the pathogenic mechanisms involved in aging, stroke, spinal cord injury, Alzheimer's disease, Huntingdon's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and the broad salutary effects of HDAC inhibition in models of these conditions may be mediated via effects on DNA damage.…”

Section: Epigenetics and Therapeutics In The Nervous System: Beyond Fmentioning

confidence: 99%

Looking Above but Not Beyond the Genome for Therapeutics in Neurology and Psychiatry: Epigenetic Proteins and RNAs Find a New Focus

Basso

Ratan

2013

Neurotherapeutics

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Chromatin Modifications Associated with DNA Double-strand Breaks Repair as Potential Targets for Neurological Diseases

Cited by 29 publications

References 118 publications

Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

NRAGE is involved in homologous recombination repair to resist the DNA-damaging chemotherapy and composes a ternary complex with RNF8–BARD1 to promote cell survival in squamous esophageal tumorigenesis

Looking Above but Not Beyond the Genome for Therapeutics in Neurology and Psychiatry: Epigenetic Proteins and RNAs Find a New Focus

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