The role of DNA repair in brain related disease pathology

Canugovi, Chandrika; Misiak, Magdalena; Ferrarelli, Leslie K.; Croteau, Deborah L.; Bohr, Vilhelm A.

doi:10.1016/j.dnarep.2013.04.010

Cited by 121 publications

(93 citation statements)

References 84 publications

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“…Moreover, it has been shown that HSV-1 lytic infection induces Egr1 in rabbit corneal cells (40). Oxidative stress is capable of initiating the DDR (41) and is reported to enhance the expression of Egr1 (42), and HSV-1 has the ability to induce neuronal oxidative stress (43). With these observations and our data, we propose that oxidative stress and/or activation of DDR during acute HSV-1 infection of neurons stimulates p35 levels via Egr1 (Fig.…”

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confidence: 66%

Herpes Simplex Virus 1 Upregulates p35, Alters CDK-5 Localization, and Stimulates CDK-5 Kinase Activity during Acute Infection in Neurons

Mostafa

Sels

Davido

2015

J Virol

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The cyclin-dependent kinase 5 (CDK-5) activating protein, p35, is important for acute herpes simplex virus 1 (HSV-1) replication in mice. This report shows that HSV-1 increases p35 levels, changes the primary localization of CDK-5 from the nucleus to the cytoplasm, and enhances CDK-5 activity during lytic or acute infection. Infected neurons also stained positive for the DNA damage response (DDR) marker ␥H2AX. We propose that CDK-5 is activated by the DDR to protect infected neurons from apoptosis. Herpes simplex virus 1 (HSV-1) is a human pathogen that establishes lifelong latent infection in sensory neurons (1, 46). It is not well understood how the virus switches from lytic to latent infections in neurons and the mechanisms involved in reversing this switch under stress stimuli to initiate reactivation. It is vital that the neurons survive an infection by HSV-1 if the virus is to efficiently establish a latent infection or reactivate. Not surprisingly, HSV-1 has developed countermeasures to prevent neuronal apoptosis, in part, with the expression of the latency-associated transcripts (LATs) (2-4). While the contribution of viral gene products that possess antiapoptotic activities has been a major area of interest in HSV-1 research, the role of cellular factors involved in neuronal survival has received limited attention.One neuronal factor that is highly active in postmitotic neurons and is required for neuronal survival during stress is cyclindependent kinase 5 (CDK-5) (5, 6). CDK-5 regulates many neuronal processes (reviewed in reference 7) and has been shown to play important roles in both neuronal survival and death. Inactivation of CDK-5 has been shown to trigger neuronal death (8-11). On the other hand, a survival function for CDK-5 is evident when neurons are stressed (12-16). For its activation, CDK-5 binds to p35 or a related protein, p39, which also modulate CDK-5's subcellular localization (17)(18)(19)(20). Notably the activity of CDK-5 directly correlates with the levels of its major activator, p35, and both are expressed predominantly in neurons (21), which likely explains why CDK-5 is mainly active in neurons, although it is constitutively expressed in many cell types (17,22).We have previously shown that HSV-1 acute replication is impaired in the eyes and trigeminal ganglia (TG) of p35 knockout mice, reducing the establishment of latency and reactivation (23). Given this previous result, we sought to determine whether HSV-1 altered the expression or subcellular localization of the p35 and CDK-5 proteins during acute infection.HSV-1 infection induces p35 protein levels. To examine how HSV-1 acute TG infection affects p35, wild-type HSV (KOS)-infected TG were harvested 3 days postinfection, as previously described (24,25). TG sections were immunostained for both the HSV-1 immediate early protein, ICP0, used as a marker for productively infected neurons, and p35. As shown in Fig. 1A, HSV-1-infected neurons showed an increase in p35 staining compared to mock-infected cells, with a distribution that...

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confidence: 66%

Herpes Simplex Virus 1 Upregulates p35, Alters CDK-5 Localization, and Stimulates CDK-5 Kinase Activity during Acute Infection in Neurons

Mostafa

Sels

Davido

2015

J Virol

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“…The total number of mutations acquired during ageing is extremely high, and robust genomic technologies demonstrated that 3,000-13,000 genes per genome can be affected by 5,000-50,000 mutations (26). It is likely that such genomic alterations could be responsible for many health problems associated with ageing, such as neurodegeneration including Parkinson's and Alzheimer's disease (27,28). The comparison of reduced DNA-repair activity, accumulation of mutations, cancer incidence and fertility seems to be interesting from a biological point of view ( Figure 1).…”

Section: Biological Background Of Ageing and Impact On Cancer Formationmentioning

confidence: 99%

Ageing as an Important Risk Factor for Cancer

et al. 2016

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“…The past 50 years has seen mounting recognition of the enormous significance of DNA damage response (DDR) pathways in protecting against the harmful effects of this damage, and particularly our understanding of the DNA repair processes [1]. Indeed, we now understand the importance these pathways play in cancer avoidance, in protection against ageing and in ensuring normal development [3,4]. We now have a good understanding of the basic DNA repair processes, at least when considering their action on naked DNA.…”

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confidence: 99%