SPT5 stabilization of promoter-proximal RNA polymerase II

Aoi, Yuki; Takahashi, Yoh-hei; Shah, Avani; Iwanaszko, Marta; Rendleman, Emily J.; Khan, Nabiha; Cho, Byoung-Kyu; Goo, Young Ah; Ganesan, Sheetal; Kelleher, Neil L.; Shilatifard, Ali

doi:10.1016/j.molcel.2021.08.006

Cited by 52 publications

(50 citation statements)

References 71 publications

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“…2c ), which indicates that the depletion of promoter-bound Pol II is not caused by inhibited Pol II initiation 22 – 24 . Interestingly, upon VCP or proteasome inhibition, an increase of P-Ser5-modified Pol II was observed, suggesting that degradation of promoter-bound Pol II may also play a role in its turnover in undamaged conditions 74 , 75 . Together these data show that when damage loads are low and TC-NER is active, the most prominent function of VCP is to extract promoter-bound Pol II, and not elongating Pol II, from chromatin to allow its proteasomal degradation.…”

Section: Discussionmentioning

confidence: 99%

DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II

et al. 2022

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The precise regulation of RNA Polymerase II (Pol II) transcription after genotoxic stress is crucial for proper execution of the DNA damage-induced stress response. While stalling of Pol II on transcription-blocking lesions (TBLs) blocks transcript elongation and initiates DNA repair in cis, TBLs additionally elicit a response in trans that regulates transcription genome-wide. Here we uncover that, after an initial elongation block in cis, TBLs trigger the genome-wide VCP-mediated proteasomal degradation of promoter-bound, P-Ser5-modified Pol II in trans. This degradation is mechanistically distinct from processing of TBL-stalled Pol II, is signaled via GSK3, and contributes to the TBL-induced transcription block, even in transcription-coupled repair-deficient cells. Thus, our data reveal the targeted degradation of promoter-bound Pol II as a critical pathway that allows cells to cope with DNA damage-induced transcription stress and enables the genome-wide adaptation of transcription to genotoxic stress.

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Section: Discussionmentioning

confidence: 99%

DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II

et al. 2022

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“…Apart from the well-established roles of SPT5 in multiple transcriptional steps, recent studies from the Shilatifard group and our lab revealed the unexpected SPT5 function in stabilizing Pol II protein [ 19 , 20 ]. In both reports, proteolysis-targeting chimera (PROTAC)-induced degradation of endogenous SPT5 in different human cells causes an immediate, substantial degradation of the largest Pol II subunit RPB1, supporting a direct regulation of Pol II stability ( Figure 2 ).…”

Section: Stabilization Of Pol II Protein By Spt5mentioning

confidence: 99%

The pleiotropic roles of SPT5 in transcription

Song

Chen

2022

Transcription

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Initially discovered by genetic screens in budding yeast, SPT5 and its partner SPT4 form a stable complex known as DSIF in metazoa, which plays pleiotropic roles in multiple steps of transcription. SPT5 is the most conserved transcription elongation factor, being found in all three domains of life; however, its structure has evolved to include new domains and associated posttranslational modifications. These gained features have expanded transcriptional functions of SPT5, likely to meet the demand for increasingly complex regulation of transcription in higher organisms. This review discusses the pleiotropic roles of SPT5 in transcription, including RNA polymerase II (Pol II) stabilization, enhancer activation, Pol II pausing and its release, elongation, and termination, with a focus on the most recent progress of SPT5 functions in regulating metazoan transcription.

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“…Phosphorylated NELF dissociates from the paused elongation complex, while phosphorylated DSIF turns into a positive elongation factor that remains associated with elongating RNApol2. Recent studies based on acute depletion of DSIF-subunit SPT5 indeed confirm that this factor plays an essential role in both maintenance of pausing and elongation processivity ( Aoi et al, 2021 ; Hu et al, 2021 ).…”

Section: Mechanistic Overview Of Promoter Proximal Pausingmentioning

confidence: 85%

Transcription Pause and Escape in Neurodevelopmental Disorders

2022

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Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

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SPT5 stabilization of promoter-proximal RNA polymerase II

Cited by 52 publications

References 71 publications

DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II

DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II

The pleiotropic roles of SPT5 in transcription

Transcription Pause and Escape in Neurodevelopmental Disorders

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