Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair (NER) progeria

Kamileri, Irene; Karakasilioti, Ismene; Sideri, Aristea; Kosteas, Theodoros; Tatarakis, Antonis; Talianidis, Iannis; Garinis, George A.

doi:10.1073/pnas.1114941109

Cited by 49 publications

(70 citation statements)

References 30 publications

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“…These coordinated events are accompanied by active DNA demethylation that could depend on the DNA damage-inducible protein GADD45A, although its involvement remains controversial (Barreto et al, 2007; Jin et al, 2008; Schmitz et al, 2009). Consistent with these observations, the ERCC1-XPF complex has also been shown to regulate transcription initiation of genes associated with growth in mice (Kamileri et al, 2012b). …”

Section: Dna Repair Factors That Double As Transcription Factorsmentioning

confidence: 53%

“…Instead, we favor a model where XPC is recruited to promoters by gene-specific activators, or potentially through recognition of DNA bends and distortions induced by binding of nuclear hormone receptors to their cognate response elements (Nardulli and Shapiro, 1993; Robinson et al, 1998; Sugasawa et al, 2001). Assembly of the NER complex at gene promoters can be further stabilized by interactions with core components of the PIC (Kamileri et al, 2012b; Yokoi et al, 2000). Therefore, DNA repair factors may act as “facilitators” of gene activation by creating a favorable structural and epigenetic configuration for transcription in a gene- and possibly cell type-specific manner.…”

Section: Dna Repair Factors That Double As Transcription Factorsmentioning

confidence: 99%

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The Intertwined Roles of Transcription and Repair Proteins

2013

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Transcription is apparently risky business. Its intrinsic mutagenic potential must be kept in check by networks of DNA repair factors that monitor the transcription process to repair DNA lesions that could otherwise compromise transcriptional fidelity and genome integrity. Intriguingly, recent studies point to an even more direct function of DNA repair complexes as co-activators of transcription and the unexpected role of “scheduled” DNA damage/repair at gene promoters. Paradoxically, spontaneous DNA double-strand breaks also induce ectopic transcription that is essential for repair. Thus, transcription, DNA damage and repair may be more physically and functionally intertwined than previously appreciated.

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Section: Dna Repair Factors That Double As Transcription Factorsmentioning

confidence: 53%

Section: Dna Repair Factors That Double As Transcription Factorsmentioning

confidence: 99%

The Intertwined Roles of Transcription and Repair Proteins

2013

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“…Also, in addition to genomic DNA damage accumulation, ERCC1 dysfunction also results in transcriptional initiation defects which neurons in particular could be vulnerable to Kamileri et al . (2012). …”

Section: Discussionmentioning

confidence: 99%

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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SummaryMicroglia are a proliferative population of resident brain macrophages that under physiological conditions self‐renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as ‘priming’. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first‐generation G1 mTerc−/−)‐ and late‐generation (third‐generation G3 and G4 mTerc−/−) telomerase‐deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late‐generation mTerc−/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc−/− microglia are comparable with microglia derived from G1 mTerc−/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc−/− microglia mice show an enhanced pro‐inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age‐associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood–brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

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“…Microarrays, qPCR, and qPCR data analysis were performed as previously described (Kamileri et al, 2012b). Primer sequences for the genes tested by qPCR are available upon request.…”

Section: Methodsmentioning

confidence: 99%

DNA Damage Triggers a Chronic Autoinflammatory Response, Leading to Fat Depletion in NER Progeria

et al. 2013

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Lipodystrophies represent a group of heterogeneous disorders characterized by loss of fat tissue. However, the underlying mechanisms remain poorly understood. Using mice carrying an ERCC1-XPF DNA repair defect systematically or in adipocytes, we show that DNA damage signaling triggers a chronic auto-inflammatory response leading to fat depletion. Ercc1−/− and aP2-Ercc1f/− fat depots show extensive gene expression similarities to lipodystrophic Pparγldi/+ animals along with focal areas of ruptured basement membrane, the reappearance of primary cilia, necrosis, fibrosis and a marked decrease in adiposity. We find that persistent DNA damage in aP2-Ercc1f/− fat depots and in adipocytes ex vivo trigger the induction of pro-inflammatory factors by promoting transcriptionally active histone marks and the dissociation of nuclear receptor co-repressor complexes from promoters; the response is cell-autonomous and requires ATM. Thus, persistent DNA damage-driven auto-inflammation plays a causative role in adipose tissue degeneration with important ramifications for progressive lipodystrophies and natural aging.

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Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair (NER) progeria

Cited by 49 publications

References 30 publications

The Intertwined Roles of Transcription and Repair Proteins

The Intertwined Roles of Transcription and Repair Proteins

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

DNA Damage Triggers a Chronic Autoinflammatory Response, Leading to Fat Depletion in NER Progeria

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