Treacle and TOPBP1 control replication stress response in the nucleolus

Velichko, Artem K.; Ovsyannikova, Natalia; Petrova, Nadezhda V.; Luzhin, Artem V; Vorobjeva, M. A.; Gavrikov, Alexey S.; Mishin, Alexander S.; Kireev, Igor I.; Razin, Sergey V.; Kantidze, Omar L.

doi:10.1083/jcb.202008085

Cited by 13 publications

(29 citation statements)

References 32 publications

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“…In spite of a structural organization that limits the interaction between transcription and replication, collisions must be processed. However, until recently the nucleolar RS response was unexplored and its unique features are therefore only starting to emerge ( Velichko et al, 2021 ). In order to gain insight into the nucleolar RS response, Velichko and colleagues treated cells with the RS-inducing agents, aphidicolin or hydroxyurea ( Velichko et al, 2021 ).…”

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

“…However, until recently the nucleolar RS response was unexplored and its unique features are therefore only starting to emerge ( Velichko et al, 2021 ). In order to gain insight into the nucleolar RS response, Velichko and colleagues treated cells with the RS-inducing agents, aphidicolin or hydroxyurea ( Velichko et al, 2021 ). Treatment with either aphidicolin or hydroxyurea showed accumulation of known RS response factors (ATR, CHK1, TOPBP1, RPA, BRCA1, and FANCD2) in the nucleolar interior ( Velichko et al, 2021 ).…”

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

“…In order to gain insight into the nucleolar RS response, Velichko and colleagues treated cells with the RS-inducing agents, aphidicolin or hydroxyurea ( Velichko et al, 2021 ). Treatment with either aphidicolin or hydroxyurea showed accumulation of known RS response factors (ATR, CHK1, TOPBP1, RPA, BRCA1, and FANCD2) in the nucleolar interior ( Velichko et al, 2021 ). ATR was found to drive the signaling response to RS, as elsewhere in the genome, and depletion or inhibition of ATR led to complete abrogation of TOPBP1 recruitment in the nucleolus ( Velichko et al, 2021 ).…”

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

“…Treatment with either aphidicolin or hydroxyurea showed accumulation of known RS response factors (ATR, CHK1, TOPBP1, RPA, BRCA1, and FANCD2) in the nucleolar interior ( Velichko et al, 2021 ). ATR was found to drive the signaling response to RS, as elsewhere in the genome, and depletion or inhibition of ATR led to complete abrogation of TOPBP1 recruitment in the nucleolus ( Velichko et al, 2021 ). The nucleolar interaction partner of TOPBP1 was shown to be Treacle, necessary for TOPBP1 nucleolar retention and TOPBP1-mediated ATR activation upon RS ( Figure 2A , Panel iv) ( Velichko et al, 2021 ).…”

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

“…ATR was found to drive the signaling response to RS, as elsewhere in the genome, and depletion or inhibition of ATR led to complete abrogation of TOPBP1 recruitment in the nucleolus ( Velichko et al, 2021 ). The nucleolar interaction partner of TOPBP1 was shown to be Treacle, necessary for TOPBP1 nucleolar retention and TOPBP1-mediated ATR activation upon RS ( Figure 2A , Panel iv) ( Velichko et al, 2021 ). ATR activity was therefore required for the initiation of the nucleolar RS response, but Treacle-TOPBP1 is crucial for its reinforcement.…”

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

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Treacle Sticks the Nucleolar Responses to DNA Damage Together

Gál

Nieto

Boukoura

et al. 2022

Front. Cell Dev. Biol.

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The importance of chromatin environment for DNA repair has gained increasing recognition in recent years. The nucleolus is the largest sub-compartment within the nucleus: it has distinct biophysical properties, selective protein retention, and houses the specialized ribosomal RNA genes (collectively referred to as rDNA) with a unique chromatin composition. These genes have high transcriptional activity and a repetitive nature, making them susceptible to DNA damage and resulting in the highest frequency of rearrangements across the genome. A distinct DNA damage response (DDR) secures the fidelity of this genomic region, the so-called nucleolar DDR (n-DDR). The composition of the n-DDR reflects the characteristics of nucleolar chromatin with the nucleolar protein Treacle (also referred to as TCOF1) as a central coordinator retaining several well-characterized DDR proteins in the nucleolus. In this review, we bring together data on the structure of Treacle, its known functions in ribosome biogenesis, and its involvement in multiple branches of the n-DDR to discuss their interconnection. Furthermore, we discuss how the functions of Treacle in ribosome biogenesis and in the n-DDR may contribute to Treacher Collins Syndrome, a disease caused by mutations in Treacle. Finally, we outline outstanding questions that need to be addressed for a more comprehensive understanding of Treacle, the n-DDR, and the coordination of ribosome biogenesis and DNA repair.

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Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

Section: Treacle Is a Central Regulator Of Nucleolar Stress Responsesmentioning

confidence: 99%

See 3 more Smart Citations

Treacle Sticks the Nucleolar Responses to DNA Damage Together

Gál

Nieto

Boukoura

et al. 2022

Front. Cell Dev. Biol.

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Pre‐rRNA Facilitates TopBP1‐Mediated DNA Double‐Strand Break Response

Xin

Gai

et al. 2023

Advanced Science

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In response to genotoxic stress‐induced DNA damage, TopBP1 mediates ATR activation for signaling transduction and DNA damage repair. However, the detailed molecular mechanism remains elusive. Here, using unbiased protein affinity purification and RNA sequencing, it is found that TopBP1 is associated with pre‐ribosomal RNA (pre‐rRNA). Pre‐rRNA co‐localized with TopBP1 at DNA double‐strand breaks (DSBs). Similar to pre‐rRNA, ribosomal proteins also colocalize with TopBP1 at DSBs. The recruitment of TopBP1 to DSBs is suppressed when cells are transiently treated with RNA polymerase I inhibitor (Pol I‐i) to suppress pre‐rRNA biogenesis but not protein translation. Moreover, the BRCT4‐5 of TopBP1 recognizes pre‐rRNA and forms liquid–liquid phase separation (LLPS) with pre‐rRNA, which may be the molecular basis of DSB‐induced foci of TopBP1. Finally, Pol I‐i treatment impairs TopBP1‐associated cell cycle checkpoint activation and homologous recombination repair. Collectively, this study reveals that pre‐rRNA plays a key role in the TopBP1‐dependent DNA damage response.

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