A DNA Repair Complex Functions as an Oct4/Sox2 Coactivator in Embryonic Stem Cells

Fong, Yick W.; Inouye, Carla; Yamaguchi, Teppei; Cattoglio, Claudia; Grubisic, Ivan; Tjian, Robert

doi:10.1016/j.cell.2011.08.038

Cited by 148 publications

(261 citation statements)

References 58 publications

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“…Furthermore, in response to DNA damage, human Rad23B was found to interact with ubiquitylated p53, localize at chromatin and accumulate at the p21 promoter 59 . In addition, in mouse embryonic stem cells, several components of the NER complex, including Rad23B, have been shown to act as an Oct4/ Sox2 co-activator complex that associates with chromatin and is required for stem cell maintenance 60 . Recruitment of NER factors to active promoters has also been reported in HeLa cells in the absence of DNA damage 61 .…”

Section: Discussionmentioning

confidence: 99%

dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes

et al. 2015

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dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here we report that dDsk2 plays a nonproteolytic function in transcription regulation. dDsk2 interacts with the dHP1c complex, localizes at promoters of developmental genes and is required for transcription. Through the ubiquitin-binding domain, dDsk2 interacts with H2Bub1, a modification that occurs at dHP1c complex-binding sites. H2Bub1 is not required for binding of the complex; however, dDsk2 depletion strongly reduces H2Bub1. Co-depletion of the H2Bub1 deubiquitylase dUbp8/Nonstop suppresses this reduction and rescues expression of target genes. RNA polymerase II is strongly paused at promoters of dHP1c complex target genes and dDsk2 depletion disrupts pausing. Altogether, these results suggest that dDsk2 prevents dUbp8/Nonstop-dependent H2Bub1 deubiquitylation at promoters of dHP1c complex target genes and regulates RNA polymerase II pausing. These results expand the catalogue of nonproteolytic functions of ubiquitin receptors to the epigenetic regulation of chromatin modifications.

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Section: Discussionmentioning

confidence: 99%

dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes

et al. 2015

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“…It is possible that no one single chromatin modification may be responsible for the inability of CS and XP/ CS cells to restart transcription, but, rather, a combination of several deficiencies may create a "perfect storm" for the subsequent heterochromatinization of these promoters. It is not surprising that XPD mutations result in a chromatin dysregulation, as more recent studies place NER factors at the intersection between transcription and repair by regulating chromatin structure (24,(29)(30)(31).…”

Section: Sirt1 Mediates Repression Of Hk Genes In Xp-d/cs Cells After Uvmentioning

confidence: 99%

“…The fact that the so-called global transcriptional arrest displayed by XP/CS and CS cells excludes genes that are activated upon DNA damage, such as p53-dependent genes, suggests that there must be an active transcriptional repression process, rather than a physical blocking of transcription. In this regard, CSB and other NER factors have been shown to affect chromatin remodeling for optimal transcription initiation (24,(29)(30)(31).…”

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confidence: 99%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

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

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Specific mutations in the XPD subunit of transcription factor IIH result in combined xeroderma pigmentosum (XP)/Cockayne syndrome (CS), a severe DNA repair disorder characterized at the cellular level by a transcriptional arrest following UV irradiation. This transcriptional arrest has always been thought to be the result of faulty transcription-coupled repair. In the present study, we showed that, following UV irradiation, XP-D/CS cells displayed a gross transcriptional dysregulation compared with "pure" XP-D cells or WT cells. Furthermore, global RNA-sequencing analysis showed that XP-D/CS cells repressed the majority of genes after UV, whereas pure XP-D cells did not. By using housekeeping genes as a model, we demonstrated that XP-D/CS cells were unable to reassemble these gene promoters and thus to restart transcription after UV irradiation. Furthermore, we found that the repression of these promoters in XP-D/CS cells was not a simple consequence of deficient repair but rather an active heterochromatinization process mediated by the histone deacetylase Sirt1. Indeed, RNA-sequencing analysis showed that inhibition of and/or silencing of Sirt1 changed the chromatin environment at these promoters and restored the transcription of a large portion of the repressed genes in XP-D/CS cells after UV irradiation. Our work demonstrates that a significant part of the transcriptional arrest displayed by XP-D/CS cells arises as a result of an active repression process and not simply as a result of a DNA repair deficiency. This dysregulation of Sirt1 function that results in transcriptional repression may be the cause of various severe clinical features in patients with XP-D/ CS that cannot be explained by a DNA repair defect.nucleotide excision repair | sirtuins | aging | progeria

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“…Aiming to discern the biochemical pathways required for the efficient and safe reprogramming of adult somatic cells into iPSCs, recent studies have shown the relevance of telomere homeostasis [2][3][4], signal transducers, and DNA repair proteins [4][5][6][7] in cell reprogramming. These results have shown that a significant DNA stress-reflected by an increased number of DNA double strand breaks (DSBs)-is produced during the reprogramming process.…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Impaired Cell Reprogramming in Nonhomologous End Joining Deficient Cells

et al. 2013

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Although there is an increasing interest in defining the role of DNA damage response mechanisms in cell reprogramming, the relevance of proteins participating in nonhomologous end joining (NHEJ), a major mechanism of DNA double-strand breaks repair, in this process remains to be investigated. Herein, we present data related to the reprogramming of primary mouse embryonic fibroblasts (MEF) from severe combined immunodeficient (Scid) mice defective in DNA-PKcs, a key protein for NHEJ. Reduced numbers of induced pluripotent stem cell (iPSC) colonies were generated from Scid cells using reprogramming lentiviral vectors (LV), being the reprogramming efficiency fourfold to sevenfold lower than that observed in wt cells. Moreover, these Scid iPSC-like clones were prematurely lost or differentiated spontaneously. While the Scid mutation neither reduce the proliferation rate nor the transduction efficacy of fibroblasts transduced with reprogramming LV, both the expression of SA-b-Gal and of P16/INK 4a senescence markers were highly increased in Scid versus wt MEFs during the reprogramming process, accounting for the reduced reprogramming efficacy of Scid MEFs. The use of improved Sleeping Beauty transposon/transposase systems allowed us, however, to isolate DNA-PKcs-deficient iPSCs which preserved their parental genotype and hypersensitivity to ionizing radiation. This new disease-specific iPSC model would be useful to understand the physiological consequences of the DNA-PKcs mutation during development and would help to improve current cell and gene therapy strategies for the disease.

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A DNA Repair Complex Functions as an Oct4/Sox2 Coactivator in Embryonic Stem Cells

Cited by 148 publications

References 58 publications

dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes

dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Brief Report: Impaired Cell Reprogramming in Nonhomologous End Joining Deficient Cells

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