The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome

Wu, Ronghu; Pellman, David; Walter, Johannes C.

doi:10.1016/j.tcb.2020.11.007

Cited by 24 publications

(20 citation statements)

References 85 publications

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“…In good agreement with our data, coordinated cleavage of stalled replication forks in mitosis was recently hypothesized to yield SCEs, at the cost of local deletions (Wu et al, 2021). This process requires that the stalled replication forks flanking the under-replicated DNA are cleaved either at both leading strands, or at both lagging strands (Fig.…”

Section: Discussionsupporting

confidence: 92%

Sister chromatid exchanges induced by perturbed replication are formed independently of homologous recombination factors

Heijink

Stok

Porubský

et al. 2021

Preprint

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Sister chromatid exchanges (SCEs) are products of joint DNA molecule resolution, and are considered to form through homologous recombination (HR). Indeed, upon generation of irradiation-induced DNA breaks, SCE induction was compromised in cells deficient for canonical HR factors BRCA1, BRCA2 and RAD51. Contrarily, replication-blocking agents, including PARP inhibitors, induced SCEs independently of BRCA1, BRCA2 and RAD51. PARP inhibitor-induced SCEs were enriched at common fragile sites (CFSs), and were accompanied by post-replicative single-stranded DNA (ssDNA) gaps. Moreover, PARP inhibitor-induced replication lesions were transmitted into mitosis, suggesting that SCEs originate from mitotic processing of under-replicated DNA. We found that DNA polymerase theta (POLQ) was recruited to mitotic DNA lesions, and loss of POLQ resulted in reduced SCE numbers and severe chromosome fragmentation upon PARP inhibition in HR-deficient cells. Combined, our data show that PARP inhibition generates under-replicated DNA, which is transferred into mitosis and processed into SCEs, independently of canonical HR factors.

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Section: Discussionsupporting

confidence: 92%

Sister chromatid exchanges induced by perturbed replication are formed independently of homologous recombination factors

Heijink

Stok

Porubský

et al. 2021

Preprint

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“…Ubiquitylation of the DPC also aids CMG bypass ( Sparks et al, 2019 ). TRAIP is proposed to bind the leading edge of the replisome to fulfill this role which also positions it to ubiquitylate an adjacent CMG after fork convergence at an ICL ( Wu et al, 2019 , 2021 ). Following bypass, CMG progression is initially slow due to uncoupling ( Figure 7C ).…”

Section: Traversal Of Impediments To Cmg Translocationmentioning

confidence: 99%

“…In Xenopus extracts, ICL repair occurs following fork convergence at the lesion ( Zhang et al, 2015 ). Here, TRAIP-dependent ubiquitylation of CMG stimulates recruitment of the NEIL3 glycosylase to resolve psoralen and abasic ICLs ( Wu et al, 2021 ). If NEIL3 fails to unhook the crosslink, continued ubiquitylation of CMG by TRAIP triggers replisome disassembly to permit repair of the ICL by the Fanconi anemia pathway ( Wu et al, 2021 ).…”

Section: Traversal Of Impediments To Cmg Translocationmentioning

confidence: 99%

“…Here, TRAIP-dependent ubiquitylation of CMG stimulates recruitment of the NEIL3 glycosylase to resolve psoralen and abasic ICLs ( Wu et al, 2021 ). If NEIL3 fails to unhook the crosslink, continued ubiquitylation of CMG by TRAIP triggers replisome disassembly to permit repair of the ICL by the Fanconi anemia pathway ( Wu et al, 2021 ). Since both pathways depend on fork convergence, they cannot be considered as mechanisms to maintain progression of individual replisomes.…”

Section: Traversal Of Impediments To Cmg Translocationmentioning

confidence: 99%

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Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

Guilliam

2021

Front. Mol. Biosci.

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The eukaryotic replisome coordinates template unwinding and nascent-strand synthesis to drive DNA replication fork progression and complete efficient genome duplication. During its advancement along the parental template, each replisome may encounter an array of obstacles including damaged and structured DNA that impede its progression and threaten genome stability. A number of mechanisms exist to permit replisomes to overcome such obstacles, maintain their progression, and prevent fork collapse. A combination of recent advances in structural, biochemical, and single-molecule approaches have illuminated the architecture of the replisome during unperturbed replication, rationalised the impact of impediments to fork progression, and enhanced our understanding of DNA damage tolerance mechanisms and their regulation. This review focusses on these studies to provide an updated overview of the mechanisms that support replisomes to maintain their progression on an imperfect template.

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“…TRAIP has several functions related to DNA repair (reviewed in Wu et al, 2020). TRAIP localizes to DNA double-strand breaks, where it recruits other factors and promotes H2B monoubiquitylation to stimulate repair (Han et al, 2019; Soo Lee et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Traip Mitotic Function Controls Brain Size

2021

Preprint

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Microcephaly is a developmental failure to achieve proper brain size and neuron number. Mutations in diverse genes are linked to microcephaly, including several with DNA damage repair (DDR) functions; however, it is not well understood how these DDR gene mutations limit brain size. One such gene is TRAIP, which has multiple known functions in DDR. We characterized the Drosophila ortholog Traip, finding that loss of Traip causes a brain-specific defect in the Mushroom Body (MB). Traip mutant (traip-) MBs had reduced size and fewer neurons, but no neurodegeneration, consistent with human primary microcephaly disorders. Reduced neuron numbers in traip- were explained by premature caspase-dependent cell death of MB neuroblasts (MB-NBs). Many traip- MB-NBs had prominent chromosome bridges in anaphase, along with polyploidy, aneuploidy, or micronuclei. We found no evidence for an interphase DNA repair role for Traip in MB-NBs; instead, proper MB development requires Traip function during mitosis, where Traip localizes to centrosomes and mitotic spindles. Our results suggest that proper brain size is ensured by the recently described role for TRAIP in unloading stalled replication forks in mitosis, which suppresses DNA bridges and neural stem cell death to promote proper neuron number. Further, the mitotic nature of traip- MB-NB defects and Traip localization suggest a closer etiological link between DDR microcephaly genes like Traip and the centrosome/spindle-related genes more commonly associated with microcephaly.

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The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome

Cited by 24 publications

References 85 publications

Sister chromatid exchanges induced by perturbed replication are formed independently of homologous recombination factors

Sister chromatid exchanges induced by perturbed replication are formed independently of homologous recombination factors

Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

Traip Mitotic Function Controls Brain Size

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