A Rad26–Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage

Woudstra, Elies C.; Gilbert, Chris; Fellows, Jane; Jansen, Lars; Brouwer, Jaap; Erdjument‐Bromage, Hediye; Tempst, Paul; Svejstrup, Jesper Q.

doi:10.1038/415929a

Cited by 216 publications

(265 citation statements)

References 28 publications

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“…It has been proposed that ubiquitylation and subsequent degradation of the damage arrested RNAPII will provide the required accessibility for TC-NER (Bregman et al 1996). However, more recent studies have challenged this model by providing firm evidence that degradation of RNAPII only occurs as "a last resort" to clear the path from permanently arrested transcription machineries when TC-NER is not functional (Woudstra et al 2002;Anindya et al 2007). Ubiquitylation of RNAPII occurs via a highly regulated multistep process that involves monoubiquitylation of RNAPII, starting with the Nedd4 (Rsp5-Ubc5 in yeast) E3 ubiquitin ligase, followed by the action of Elongin A/B/C and Cullin5-Rbx2 (Elc1-Cul3 and Def1 in yeast) that promote lysine-48 linked polyubiquitin chains (reviewed by Wilson et al 2012).…”

Section: Fate Of a Damage Arrested Rnapiimentioning

confidence: 98%

Mammalian Transcription-Coupled Excision Repair

Vermeulen¹,

Fousteri

2013

Cold Spring Harbor Perspectives in Biology

156

116

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Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients' death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process.

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Section: Fate Of a Damage Arrested Rnapiimentioning

confidence: 98%

Mammalian Transcription-Coupled Excision Repair

Vermeulen¹,

Fousteri

2013

Cold Spring Harbor Perspectives in Biology

156

116

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“…The yeast homolog of CSB, RAD26, links transcript elongation to TCR (Gregory and Sweder 2001). Experiments in yeast suggest that RAD26, in concert with the DEF1 protein, functions to rescue stalled RNAP II at DNA lesions (Woudstra et al 2002). Although no direct connection has been made, it is possible that CSB and the Elongins cooperate to alleviate stalled RNAP II complexes at DNA lesions.…”

Section: Csbmentioning

confidence: 99%

Elongation by RNA polymerase II: the short and long of it

Sims¹,

Belotserkovskaya²,

Reinberg³

2004

Genes Dev.

612

578

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Appreciable advances into the process of transcript elongation by RNA polymerase II (RNAP II) have identified this stage as a dynamic and highly regulated step of the transcription cycle. Here, we discuss the many factors that regulate the elongation stage of transcription. Our discussion includes the classical elongation factors that modulate the activity of RNAP II, and the more recently identified factors that facilitate elongation on chromatin templates. Additionally, we discuss the factors that associate with RNAP II, but do not modulate its catalytic activity. Elongation is highlighted as a central process that coordinates multiple stages in mRNA biogenesis and maturation.The regulation of gene expression is one of the most intensely studied areas in all of science. Differential gene expression in multicellular organisms forms the foundation of cell-type specificity. Deregulation of the appropriate pattern of gene expression has profound effects on cellular function and underlies many diseases. Although there are many cellular processes that control gene expression, the most direct regulation occurs during transcription. The transcription of protein-coding genes in eukaryotes is performed by RNA polymerase II (RNAP II). Up until recently, the vast majority of studies aimed at elucidating the molecular mechanisms of transcription regulation have focused on early stages, such as the formation of a transcription initiation complex (preinitiation) and initiation (see below). For many years, transcript elongation has been thought of as the trivial addition of ribonucleoside triphosphates to the growing mRNA chain. It is now apparent that this process is a dynamic and highly regulated stage of the transcription cycle capable of coordinating downstream events. Numerous factors have been identified that specifically target the elongation stage of transcription. Importantly, multiple steps in mRNA maturation, including premRNA capping, splicing, 3Ј-end processing, surveillance, and export, are modulated through interactions with the RNAP II transcript elongation complex (TEC). It also appears that distinct elongation factors function in specific transcriptional contexts; the requirements for these specialized factors are largely unknown and highlight the need to better understand elongation in vivo. Many molecular and biochemical approaches have been used to quantify the different aspects of elongation, many of which are discussed below. It remains important to assimilate both in vitro and in vivo experimental systems when discussing what constitutes an elongation factor. An elongation factor can be defined as any molecule that affects the activities of or is associated with the TEC. We suggest that there are at least two major types of transcript elongation factors: one family, referred to as active elongation factors, and a second family, denoted as passive elongation factors. The difference resides in whether the factor affects the catalytic activity of RNAP II, regardless of whether the factor remains associate...

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“…In the yeast S. cerevisiae, TC-NER involves the mfd counterpart encoded by the Rad26 gene [27]. Similar to the bacterial TC-NER, evidence has been presented in yeast that in some situations, a damage-arrested RNA polymerase might be released from the template by a mechanism that leads to its ubiquitylation and degradation [28]. This process requires the DNA damage dependent interaction of a protein encoded by the DEF1 gene with the TC-NER specific factor Rad26.…”

Section: Transcription-coupled Nucleotide Excision Repair Requires Spmentioning

confidence: 99%

Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects

2008

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The encounter of elongating RNA polymerase II (RNAPIIo) with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPIIo-blocking DNA lesions by transcription-coupled repair (TC-NER), a specialized subpathway of nucleotide excision repair (NER). Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects (cancer) of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome (CS). Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER: CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA-E3-ubiquitin ligase complex to the stalled RNAPIIo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFIIS. The emerging picture of TC-NER is complex: repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPIIo, and requires at least two essential assembly factors (CSA and CSB), the core NER factors (except for XPC-RAD23B), and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.

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A Rad26–Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage

Cited by 216 publications

References 28 publications

Mammalian Transcription-Coupled Excision Repair

Mammalian Transcription-Coupled Excision Repair

Elongation by RNA polymerase II: the short and long of it

Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects

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