FBH1 Catalyzes Regression of Stalled Replication Forks

Fugger, Kasper; Mistrík, Martin; Neelsen, Kai J.; Yao, Qi; Zellweger, Ralph; Kousholt, Arne Nedergaard; Haahr, Peter; Chu, Wai Kit; Bártek, Jiří; Lopes, Massimo; Hickson, Ian D.; Sørensen, Claus Storgaard

doi:10.1016/j.celrep.2015.02.028

Cited by 98 publications

(88 citation statements)

References 33 publications

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“…A particularly attractive possibility is that fork reversal might occur and/or persist as a consequence of Dna2 helicase dysfunction. The resulting chicken-foot structure, which effectively contains a single-ended DNA double-strand break at the tip of the regressed DNA branch, could account for DNA damage checkpoint activation51, which we observe in Dna2 helicase-defective cells (Figs 2d and 5c). A four-way chicken-foot DNA intermediate would also be amenable to resolution by Yen1; perhaps more so than by Mus81-Mms4, which is greatly stimulated by pre-existing nicks within DNA junctions, such as those that may be present in HR-dependent joint molecules and maturing HJs prior to a final ligation step293043.…”

Section: Discussionmentioning

confidence: 72%

Replication intermediates that escape Dna2 activity are processed by Holliday junction resolvase Yen1

et al. 2016

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Cells have evolved mechanisms to protect, restart and repair perturbed replication forks, allowing full genome duplication, even under replication stress. Interrogating the interplay between nuclease-helicase Dna2 and Holliday junction (HJ) resolvase Yen1, we find the Dna2 helicase activity acts parallel to homologous recombination (HR) in promoting DNA replication and chromosome detachment at mitosis after replication fork stalling. Yen1, but not the HJ resolvases Slx1-Slx4 and Mus81-Mms4, safeguards chromosome segregation by removing replication intermediates that escape Dna2. Post-replicative DNA damage checkpoint activation in Dna2 helicase-defective cells causes terminal G2/M arrest by precluding Yen1-dependent repair, whose activation requires progression into anaphase. These findings explain the exquisite replication stress sensitivity of Dna2 helicase-defective cells, and identify a non-canonical role for Yen1 in the processing of replication intermediates that is distinct from HJ resolution. The involvement of Dna2 helicase activity in completing replication may have implications for DNA2-associated pathologies, including cancer and Seckel syndrome.

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Section: Discussionmentioning

confidence: 72%

Replication intermediates that escape Dna2 activity are processed by Holliday junction resolvase Yen1

et al. 2016

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“…A recent report has also suggested that a very early ATM activation event in response to replication stress -the sensing of regressed replication forks -is triggered by the FBH1 (encoded by FBXO18) helicase (Fugger et al, 2015). After its activation, ATM induces a wide spectrum of signal transduction pathways that connect processes involved in DNA repair, cell metabolism, bioenergetics, as well as protein translation and transcription.…”

Section: Cellular Effects Of Atm Signalingmentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

232

228

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There was an error published in J. Cell Sci. 128, 4255-4262.An incorrect citation and reference was given for the last sentence in Box 2. The correct citation and reference are: A recent review provides a detailed update on ATM and ATR inhibitors, and their potential as drug targets (Weber and Ryan, 2015).Weber, A.M. and Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 149, 124-138.The authors apologise to the readers for any confusion that this error might have caused. Although the role of both ATM and ATR in DNA repair, cell cycle regulation and apoptosis have been well studied, both still remain in the focus of current research activities owing to their role in cancer. Recent advances in the field suggest that these proteins have an additional function in maintaining cellular homeostasis under both stressed and non-stressed conditions. In this Cell Science at a Glance article and the accompanying poster, we present an overview of recent advances in ATR and ATM research with emphasis on that into the modes of ATM and ATR activation, the different signaling pathways they participate in -including those that do not involve DNA damage -and highlight their relevance in cancer. 1285

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“…In vitro studies of fork remodeling require modifications to the DNA such as mismatches at the fork junction to prevent spontaneous branch migration. Even with these modifications, there are many enzymes that can catalyze fork regression of naked DNA substrates including BLM, WRN, HLTF, FANCM, FBH1, ZRANB3, and SMARCAL1 [60–69]. …”

Section: How Does the Replication Checkpoint Prevent Fork Collapse?mentioning

confidence: 99%

“…New genetic evidence suggests that the homologous recombination protein RAD51 is essential for fork regression [79], and the FBH1 helicase also plays a role [69]. Another enzyme, RECQ1 participates in restoring replication forks that form due to low dose CPT treatment [80].…”

Section: How Does the Replication Checkpoint Prevent Fork Collapse?mentioning

confidence: 99%

Preventing replication fork collapse to maintain genome integrity

2015

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Billions of base pairs of DNA must be replicated trillions of times in a human lifetime. Complete and accurate replication once and only once per cell division cycle is essential to maintain genome integrity and prevent disease. Impediments to replication fork progression including difficult to replicate DNA sequences, conflicts with transcription, and DNA damage further add to the genome maintenance challenge. These obstacles frequently cause fork stalling, but only rarely cause a failure to complete replication. Robust mechanisms ensure that stalled forks remain stable and capable of either resuming DNA synthesis or being rescued by converging forks. However, when failures do happen the fork collapses leading to genome rearrangements, cell death and disease. Despite intense interest, the mechanisms to repair damaged replication forks, stabilize them, and ensure successful replication remain only partly understood. Different models of fork collapse have been proposed with varying descriptions of what happens to the DNA and replisome. Here, I will define fork collapse and describe what is known about how the replication checkpoint prevents it to maintain genome stability.

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FBH1 Catalyzes Regression of Stalled Replication Forks

Cited by 98 publications

References 33 publications

Replication intermediates that escape Dna2 activity are processed by Holliday junction resolvase Yen1

Replication intermediates that escape Dna2 activity are processed by Holliday junction resolvase Yen1

ATM and ATR signaling at a glance

Preventing replication fork collapse to maintain genome integrity

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