WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks

Caron, Pierre; Pankotai, Tibor; Wiegant, Wouter W.; Tollenaere, Maxim A. X.; Furst, Audrey; Bonhomme, Céline; Helfricht, Angela; Groot, Arjan de; Pastink, Albert; Vertegaal, Alfred C.O.; Luijsterburg, Martijn S.; Soutoglou, Evi; Attikum, Haico van

doi:10.1101/gad.321943.118

Cited by 86 publications

(80 citation statements)

References 65 publications

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“…Using this system, the Kastan lab disclosed the distribution of Nbs1 and ATM, and histones (Berkovich et al, 2007;Goldstein et al, 2013) at DSBs by ChIP-qPCR. This system was used by others to investigate the dynamics of the transcription machinery following I-PpoI DSB induction in RNA Polymerase II-transcribed genes, revealing a DNAPK-dependent breakinduced transcriptional arrest (Pankotai et al, 2012;Caron et al, 2019), or to investigate the DDR induced in the nucleolus (Harding et al, 2015;Warmerdam et al, 2016;Pefani et al, 2018). I-PpoI has been further applied to interrogate DSB repair mechanisms in other organisms, such as fission yeast (Sunder et al, 2012;Kuntz and O'Connell, 2013;Ohle et al, 2016) and mice (Kim et al, 2016).…”

Section: I-ppoimentioning

confidence: 99%

Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox

Vítor

Huertas

Legube

et al. 2020

Front. Mol. Biosci.

122

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To ward off against the catastrophic consequences of persistent DNA double-strand breaks (DSBs), eukaryotic cells have developed a set of complex signaling networks that detect these DNA lesions, orchestrate cell cycle checkpoints and ultimately lead to their repair. Collectively, these signaling networks comprise the DNA damage response (DDR). The current knowledge of the molecular determinants and mechanistic details of the DDR owes greatly to the continuous development of groundbreaking experimental tools that couple the controlled induction of DSBs at distinct genomic positions with assays and reporters to investigate DNA repair pathways, their impact on other DNAtemplated processes and the specific contribution of the chromatin environment. In this review, we present these tools, discuss their pros and cons and illustrate their contribution to our current understanding of the DDR.

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Section: I-ppoimentioning

confidence: 99%

Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox

Vítor

Huertas

Legube

et al. 2020

Front. Mol. Biosci.

122

View full text Add to dashboard Cite

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“…Furthermore, even a single DSB can lead to DNA-PKcs-dependent transcription silencing, suggesting that PARP1 could also be involved in this pathway. At the end of this process, the HECT E3 ubiquitin ligase, WWP2 directs the stalled RNAPII complex to proteasomal degradation [54].…”

Section: Parylation Regulates Transcription Responses During Dna Damagementioning

confidence: 99%

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

Páhi

Borsos

Pantazi

et al. 2020

Cancers

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Transcription is a multistep, tightly regulated process. During transcription initiation, promoter recognition and pre-initiation complex (PIC) formation take place, in which dynamic recruitment or exchange of transcription activators occur. The precise coordination of the recruitment and removal of transcription factors, as well as chromatin structural changes, are mediated by post-translational modifications (PTMs). Poly(ADP-ribose) polymerases (PARPs) are key players in this process, since they can modulate DNA-binding activities of specific transcription factors through poly-ADP-ribosylation (PARylation). PARylation can regulate the transcription at three different levels: (1) by directly affecting the recruitment of specific transcription factors, (2) by triggering chromatin structural changes during initiation and as a response to cellular stresses, or (3) by post-transcriptionally modulating the stability and degradation of specific mRNAs. In this review, we principally focus on these steps and summarise the recent findings, demonstrating the mechanisms through which PARylation plays a potential regulatory role during transcription and DNA repair.

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“…7d). Similarly, immunoprecipitation of GFP-tagged RNAPII from cells stably expressing GFP-RPB1 34 , revealed robust UV-induced interactions with both CSB and CSA (Fig. 7e), demonstrating that our conditions do allow us to detect interactions with TCR proteins after UV irradiation.…”

Section: Knockout Of Hmgn1 and Hmgn2 Does Not Affect Uv Sensitivitymentioning

confidence: 54%

Human HMGN1 and HMGN2 are not required for transcription-coupled DNA repair

Apelt

Zoutendijk

Gout

et al. 2020

Sci Rep

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Transcription-coupled repair (TCR) removes DNA lesions from the transcribed strand of active genes. Stalling of RNA polymerase II (RNAPII) at DNA lesions initiates TCR through the recruitment of the CSB and CSA proteins. The full repertoire of proteins required for human TCR – particularly in a chromatin context - remains to be determined. Studies in mice have revealed that the nucleosome-binding protein HMGN1 is required to enhance the repair of UV-induced lesions in transcribed genes. However, whether HMGN1 is required for human TCR remains unaddressed. Here, we show that knockout or knockdown of HMGN1, either alone or in combination with HMGN2, does not render human cells sensitive to UV light or Illudin S-induced transcription-blocking DNA lesions. Moreover, transcription restart after UV irradiation was not impaired in HMGN-deficient cells. In contrast, TCR-deficient cells were highly sensitive to DNA damage and failed to restart transcription. Furthermore, GFP-tagged HMGN1 was not recruited to sites of UV-induced DNA damage under conditions where GFP-CSB readily accumulated. In line with this, HMGN1 did not associate with the TCR complex, nor did TCR proteins require HMGN1 to associate with DNA damage-stalled RNAPII. Together, our findings suggest that HMGN1 and HMGN2 are not required for human TCR.

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WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks

Cited by 86 publications

References 65 publications

Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox

Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

Human HMGN1 and HMGN2 are not required for transcription-coupled DNA repair

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