TRAIP regulates replication fork recovery and progression via PCNA

Feng, Wei; Guo, Yingying; Huang, Jun; Deng, Yiqun; Zang, Jianye; Huen, Michael S.Y.

doi:10.1038/celldisc.2016.16

Cited by 40 publications

(61 citation statements)

References 45 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The E3 ubiquitin ligase TRAIP counteracts replication stress to maintain genome integrity (Feng et al, 2016; Harley et al, 2016; Hoffmann et al, 2016; Soo Lee et al, 2016), and we recently found that it is bound to replication forks that have stalled at a LacR array (Dewar et al, 2017). We therefore asked whether TRAIP is responsible for CMG unloading from stalled forks in mitosis.…”

Section: Resultsmentioning

confidence: 99%

Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements

Deng

Kochenova

et al. 2018

Preprint

View full text Add to dashboard Cite

22DNA replication errors generate complex chromosomal rearrangements and thereby 23 contribute to tumorigenesis and other human diseases. Although the events that trigger 24 these errors are not well understood, one candidate is mitotic entry before the 25 completion of DNA replication. To address the impact of mitosis on DNA replication, we 26 employed Xenopus egg extracts. When mitotic CDK (Cyclin B1-CDK1) is used to drive 27 these extracts into mitosis, the E3 ubiquitin ligase TRAIP promotes ubiquitylation of the 28 replicative CMG (CDC45/MCM2-7/GINS) helicase at stalled forks and at forks that have 29 completed DNA synthesis. In both cases, ubiquitylation is followed by CMG extraction 30 from chromatin by the CDC48/p97 ATPase. At stalled forks, CMG removal results in 31 fork breakage and complex end joining events involving deletions and template-32 switching. Our results identify TRAIP-dependent replisome disassembly as a novel 33 trigger of replication fork collapse and propose it underlies complex DNA 34 rearrangements in mitosis. 35 3 HIGHLIGHTS 36 1. TRAIP-dependent MCM7 ubiquitylation removes all CMGs from chromatin in 37 mitosis 38 2. CMG unloading from stalled forks causes replication fork breakage 39 3. Replication fork breakage in mitosis causes complex rearrangements 40 4. New model of replication fork collapse 41 42 43Genome evolution occurs through the gradual accrual of genetic changes or in a 44 saltatory manner, with bursts of chromosomal alterations originating from single 45 catastrophic events (Holland and Cleveland, 2012; Leibowitz et al., 2015; Liu et al., 46 2011; Stephens et al., 2011). Many chromosomal alterations can be traced to DNA 47 breaks that arise during DNA replication (Hills and Diffley, 2014; Mankouri et al., 2013; 48 Techer et al., 2017). However, there is an ongoing debate about when and how 49 replication fork breakage is triggered (Toledo et al., 2017). 50In normal cells, multiple cell cycle regulatory controls and error correction 51 mechanisms prevent DNA replication errors (Hills and Diffley, 2014). Cells prepare for 52 DNA replication in the G1 phase of the cell cycle, when pairs of MCM2-7 ATPases are 53 recruited to each origin ("licensing"). In S phase, cyclin-dependent kinase (CDK) 54 promotes the association of CDC45 and GINS with MCM2-7, leading to formation of the 55 replicative CMG helicase complex (CDC45-MCM2-7-GINS) ("initiation"). CMG 56 unwinding of the origin nucleates the assembly of two DNA replication forks that travel 57 away from the origin, copying DNA as they go ("elongation"). When converging forks 58 from adjacent origins meet, the replisome is disassembled ("termination"). Replisome 59 disassembly in S phase requires the E3 ubiquitin ligase CRL2 Lrr1 , which ubiquitylates 60 the MCM7 subunit of CMG, leading to CMG's extraction from chromatin by the p97 61 ATPase (Dewar et al., 2017; Sonneville et al., 2017). In the absence of CRL2 Lrr1 , CMGs 62 persist on chromatin until mitosis, but are then removed by a secondary, p97-dependent ...

show abstract

Section: Resultsmentioning

confidence: 99%

Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements

Deng

Kochenova

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…A relevant substrate for TRAIP has not been identified so far, although its inactivation also reduces γH2AX formation (Harley et al, 2016). It was proposed that TRAIP may participate in removing PCNA from stalled forks under certain conditions (Feng et al, 2016). Indeed, It has been previously shown that upon treatment with replication inhibitors such as hydroxyurea, ATR-dependent fork remodeling results in active unloading of PCNA (Dungrawala et al, 2015; Yu et al, 2014).…”

Section: Other Genome Stability Mechanismsmentioning

confidence: 99%

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

2017

View full text Add to dashboard Cite

Proliferating Cell Nuclear Antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it. Through its many protein interactions and various post-translational modifications, PCNA has far-reaching impacts on a myriad of cellular functions.

show abstract

“…Tandem affinity purification -mass spectrometry Affinity purification of PRMT6 protein complexes was carried out as described previously (Feng et al, 2016) on whole cell lysates. Stable clones of 293T cells expressing PRMT6 with C-terminally tagged with SFB were harvested and lysed in NETN buffer for 30 mins on ice.…”

Section: Contact For Reagents and Resource Sharingmentioning

confidence: 99%

PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

Chan

Zhou

et al. 2018

Cell Reports

View full text Add to dashboard Cite

show abstract

TRAIP regulates replication fork recovery and progression via PCNA

Cited by 40 publications

References 45 publications

Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements

Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

Contact Info

Product

Resources

About