Cell Cycle Activation in Postmitotic Neurons is Essential for DNA Repair

Schwartz, Elena; Smilenov, Lubomir B.; Price, Mitchell R.; Osredkar, Tracy; Baker, Ronald A.; Ghosh, Sourish; Shi, Fu Dong; Vollmer, Timothy; Lencinas, Alejandro; Stearns, Diane M.; Gorospe, Myriam; Kruman, Inna I.

doi:10.4161/cc.6.3.3752

Cited by 82 publications

(75 citation statements)

References 67 publications

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“…31 Though several in vivo/in vitro studies showed that CDK inhibitors prevent neuronal apoptosis induced by DNA damage or excitotoxic stress, 31,32 the extent to which cell-cycle proteins are involved in excitotoxicity seems to depend on the insult's strength, oxidative stress, and resulting DNA damage as well as on neurons ability to overcome the acute stress. 31,33 Furthermore, although certain cell-cycle components are essential to DNA repair and neuronal survival, entry into S phase and DNA replication are thought to be lethal for postmitotic neurons. 32,33 Thus, in vivo, Rb stimulation by CXCL12 could counteract the effect of toxic insults that trigger reentry of neurons into cell cycle, such as oxidative stress and DNA damage, which are the underlying cause of neuropathologies associated to excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…31,33 Furthermore, although certain cell-cycle components are essential to DNA repair and neuronal survival, entry into S phase and DNA replication are thought to be lethal for postmitotic neurons. 32,33 Thus, in vivo, Rb stimulation by CXCL12 could counteract the effect of toxic insults that trigger reentry of neurons into cell cycle, such as oxidative stress and DNA damage, which are the underlying cause of neuropathologies associated to excitotoxicity. 34,35 However, in the present study Rb impairment (and maybe cell cycle reentry) is not essential to NMDA toxicity as the effect of NMDA is not altered by Rb silencing.…”

Section: Discussionmentioning

confidence: 99%

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The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein

et al. 2008

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Postmitotic neurons need to keep their cell cycle under control to survive and maintain a differentiated state. This study aims to test the hypothesis that the chemokine CXCL12 regulates neuronal survival and differentiation by promoting Rb function, as suggested by previous studies showing that CXCL12 protects neurons from apoptosis induced by Rb loss. To this end, the effect of CXCL12 on Rb expression and transcriptional activity and the role of Rb in CXCL12-induced neuronal survival were studied. CXCL12 increases Rb protein and RNA levels in rat cortical neurons. The chemokine also stimulates an exogenous Rb promoter expressed in these neurons and counteracts the inhibition of the Rb promoter induced by E2F1 overexpression. Furthermore CXCL12 stimulates Rb activity as a transcription repressor. The effects of CXCL12 are mediated by its specific receptor CXCR4, and do not require the presence of glia. Finally, shRNA studies show that Rb expression is crucial to the neuroprotective activity of CXCL12 as indicated by NMDA-neurotoxicity assays. These findings suggest that proper CXCR4 stimulation in the mature CNS can prevent impairment of the Rb-E2F pathway and support neuronal survival. This is important to maintain CNS integrity in physiological conditions and prevent neuronal injury and loss typical of many neurodegenerative and neuroinflammatory conditions. Cell Death and Differentiation ( 1,2 Stimulation of CXCR4 by its endogenous ligand leads to activation of intracellular pathways affecting neuronal survival, migration, and neurotransmission.1,3 For instance, CXCR4 stimulates the PI3K/Akt pathway and regulates cell-cycle proteins in neurons. [3][4][5][6] Under pathological conditions at least some of these essential CXCR4 functions are compromised, leading to neuronal dysfunction/death. 1,7 Thus, a complete understanding of the effects of CXCR4 activation in the brain has important physiological and pathological implications.Rb is a well-known transcriptional repressor, which controls cell-cycle progression, differentiation/survival, and genomic integrity. Rb is also implicated in fundamental CNS developmental processes such as, neuronal migration, differentiation, and neurite extension. 8,9 The effects of Rb on cell survival are primarily due to regulation of members of the E2F family of transcription factors, though Rb can also directly inactivate proapoptotic proteins, such as pp32.10 E2F proteins stimulate expression of genes promoting cell-cycle progression in proliferating cells, whereas they induce apoptotic genes in differentiated cells, including neurons.11 Rb is phosphorylated at several phosphoacceptor sites by specific kinases. 12 Hence, the immediate effect of Rb phosphorylation is to remove Rb from its specific promoters, leading to inhibition of Rb-dependent gene repression. Rb phosphorylation results in enhanced E2F1 transcriptional activity culminating in death of postmitotic neurons.11 Alterations of Rb/E2F pathway were reported in various neuropathologies, such as Parkinson's and Alzhei...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein

et al. 2008

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“…For example, the DNA-damage response in mitotic cells results in cell-cycle arrest involving the major cell-cycle machinery. In postmitotic cells, DNA damage may result in cell-cycle activation and subsequent arrest, leading to deleterious events in this cell population as well (110,160). However, we have evolved a series of DNArepair pathways to correct the damage, including direct repair (DR), base-excision repair (BER), nucleotide-excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and nonhomologous end joining (NHEJ) (85,86) (Fig.…”

Section: Dna-repair Pathwaysmentioning

confidence: 99%

Redox Regulation of DNA Repair: Implications for Human Health and Cancer Therapeutic Development

Luo

Kelley

et al. 2010

Antioxidants & Redox Signaling

113

136

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Redox reactions are known to regulate many important cellular processes. In this review, we focus on the role of redox regulation in DNA repair both in direct regulation of specific DNA repair proteins as well as indirect transcriptional regulation. A key player in the redox regulation of DNA repair is the base excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) in its role as a redox factor. APE1 is reduced by the general redox factor thioredoxin, and in turn reduces several important transcription factors that regulate expression of DNA repair proteins. Finally, we consider the potential for chemotherapeutic development through the modulation of APE1's redox activity and its impact on DNA repair. Antioxid. Redox Signal. 12, 1247-1269.

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“…For example, an increase in cyclin D1 levels and its associated kinase activity is observed following DNA damage (an upstream mediator of stroke damage) and ischemic insult (5, 7, 9 -11). In addition, treatment with pharmacologic cyclin-dependent kinase (Cdk) 3 inhibitors such as flavopiridol protects neurons from both DNA damage-and ischemia-induced cell death (4,6,7). Expression of a dominant negative form of Cdk4, an important regulator of the G 1 /S phase of the cell cycle, is protective following DNA damage and global cerebral ischemia (5,9).…”

mentioning

confidence: 99%

Regulation of Ischemic Neuronal Death by E2F4-p130 Protein Complexes

Iyirhiaro

Zhang

Estey

et al. 2014

Journal of Biological Chemistry

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Background:The contribution of E2F4 to hypoxic/ischemic neuronal death is understood poorly. Results: Loss of E2F4 leads to an increase in B-Myb and contributes to hypoxic/ischemic neuronal death. Conclusion: E2F4 is important for survival following hypoxic/ischemic neuronal death. Significance: Targeting E2F4-repressive functions may be important in maintaining neuronal survival under hypoxic/ischemic conditions.

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Cell Cycle Activation in Postmitotic Neurons is Essential for DNA Repair

Cited by 82 publications

References 67 publications

The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein

The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein

Redox Regulation of DNA Repair: Implications for Human Health and Cancer Therapeutic Development

Regulation of Ischemic Neuronal Death by E2F4-p130 Protein Complexes

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