TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

Moudrý, Pavel; Watanabe, Kenji; Wolanin, Kamila; Bártková, Jiřina; Wassing, Isabel E.; Watanabe, Sugiko; Strauss, Robert; Pedersen, Rune Troelsgaard; Oestergaard, Vibe H.; Lisby, Michael; Andújar-Sánchez, Miguel; Maya-Mendoza, Apolinar; Esashi, Fumiko; Lukáš, Jiří; Bártek, Jiří

doi:10.1083/jcb.201507042

Cited by 76 publications

(100 citation statements)

References 29 publications

(38 reference statements)

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“…[49][50][51][52][53] Though detailed mechanisms remain to be elucidated, recent studies suggest that TopBP1 executes these functions by interacting with specific partner proteins. One study found that human TopBP1 binds to Pololike kinase and stimulates phosphorylation of the recombinase Rad51 at serine 14, a modification important for Rad51 recruitment to chromatin and recombination initiation.…”

Section: Dpb11 and Homologs Function In Recombinational Repairmentioning

confidence: 99%

“…One study found that human TopBP1 binds to Pololike kinase and stimulates phosphorylation of the recombinase Rad51 at serine 14, a modification important for Rad51 recruitment to chromatin and recombination initiation. 53 Others studies have shown that TopBP1 aids the resolution of DNA non-disjunctions by recruiting the scaffold SLX4 and Topoisomerase 2A to chromatin. 52,54 Furthermore TopBP1 can promote DNA synthesis at under-replicated regions during mitosis by unknown mechanisms.…”

Section: Dpb11 and Homologs Function In Recombinational Repairmentioning

confidence: 99%

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Multi-BRCT scaffolds use distinct strategies to support genome maintenance

2016

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Genome maintenance requires coordinated actions of diverse DNA metabolism processes. Scaffolding proteins, such as those containing multiple BRCT domains, can influence these processes by collaborating with numerous partners. The best-studied examples of multi-BRCT scaffolds are the budding yeast Dpb11 and its homologues in other organisms, which regulate DNA replication, repair, and damage checkpoints. Recent studies have shed light on another group of multi-BRCT scaffolds, including Rtt107 in budding yeast and related proteins in other organisms. These proteins also influence several DNA metabolism pathways, though they use strategies unlike those employed by the Dpb11 family of proteins. Yet, at the same time, these 2 classes of multi-BRCT proteins can collaborate under specific situations. This review summarizes recent advances in our understanding of how these multi-BRCT proteins function in distinct manners and how they collaborate, with a focus on Dpb11 and Rtt107.

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Section: Dpb11 and Homologs Function In Recombinational Repairmentioning

confidence: 99%

Section: Dpb11 and Homologs Function In Recombinational Repairmentioning

confidence: 99%

Multi-BRCT scaffolds use distinct strategies to support genome maintenance

2016

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“…In this work, the authors first identified TOP BP1 as a hit in a high-content RNAi screen for proteins whose depletion resulted in higher toxicity after olaparib treatment in osteosarcoma cells, which suggests that loss or inactivation of TOP BP1 predicts the response of cancer cells to this drug. Moudry et al (2016) observed that RNAi-mediated knockdown of TOP BP1 in cancer cells treated with olaparib increased the level of DNA damage and induced DNA DSB markers. The researchers subsequently examined whether olaparib sensitivity reflected defective HR in TOP BP1-depleted cells by measuring HR activity through several parameters and confirmed that TOP BP1-depleted cells showed reduced HR activity.…”

mentioning

confidence: 99%

“…Although the work of Moudry et al (2016) is the first to show a clear role for TOP BP1 in RAD51 loading, studies in budding yeast have proposed links between the TOP BP1 orthologue Dpb11 and HR-mediated repair. It was shown that the temperature-sensitive dpb11-1 mutant displays a sensitivity to DNA damage that is not further increased by deletion of RAD51, suggesting that Dpb11 functions in HR repair (Ogiwara et al, 2006).…”

mentioning

confidence: 99%

“…In this issue, Moudry et al add to the list of crucial TOP BP1 roles in genome biology and reveal that TOP BP1 is also required for proper repair of double strand breaks (DSBs) by homologous recombination (HR). Moudry et al (2016) report that depletion of TOP BP1 makes cells highly sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib, a drug known to sensitize cells with an already dysfunctional HR machinery. In particular, olaparib hypersensitizes cells that carry mutations in the bona fide HR factors and tumor suppressors BRCA1 or BRCA2.…”

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TOPBP1 takes RADical command in recombinational DNA repair

Liu¹,

Smolka²

2016

J Exp Med

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Proper replication and maintenance of the eukaryotic genome requires the involvement of the scaffolding protein TOP BP1. Over the last 20 years, studies in yeast, frog, and mammals have revealed conserved roles for TOP BP1 in initiation of DNA replication and activation of DNA damage signaling. TOP BP1 has been shown to assemble ternary protein complexes necessary to jump-start DNA replication or to initiate DNA damage signaling events by recognizing distinct phosphoproteins via its multiple BRCA1 C terminus (BRCT) domains (Fig. 1 D ;Wardlaw et al., 2014). In this issue, Moudry et al. add to the list of crucial TOP BP1 roles in genome biology and reveal that TOP BP1 is also required for proper repair of double strand breaks (DSBs) by homologous recombination (HR). Moudry et al. (2016) report that depletion of TOP BP1 makes cells highly sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib, a drug known to sensitize cells with an already dysfunctional HR machinery. In particular, olaparib hypersensitizes cells that carry mutations in the bona fide HR factors and tumor suppressors BRCA1 or BRCA2. In this work, the authors first identified TOP BP1 as a hit in a high-content RNAi screen for proteins whose depletion resulted in higher toxicity after olaparib treatment in osteosarcoma cells, which suggests that loss or inactivation of TOP BP1 predicts the response of cancer cells to this drug. Moudry et al. (2016) observed that RNAi-mediated knockdown of TOP BP1 in cancer cells treated with olaparib increased the level of DNA damage and induced DNA DSB markers. The researchers subsequently examined whether olaparib sensitivity reflected defective HR in TOP BP1-depleted cells by measuring HR activity through several parameters and confirmed that TOP BP1-depleted cells showed reduced HR activity.The HR process encompasses several phases, including end resection and chromatin loading of RPA and RAD51, which can be visualized by formation of microscopically detectable foci. Moudry et al. (2016) searched for which step of HR was compromised in cells depleted for TOP BP1 and found that DNA end resection, i.e., the processing of the 5′ recessed end that exposes a 3′ overhang used for homology search, seemed not to be affected, as evaluated by the amounts of single stranded DNA detected by BrdU incorporation under nondenaturing conditions. Interestingly, they found that the next key stage in HR, in which the RAD51 recombinase protein is loaded at these 3′ overhangs (Fig. 1 A), was greatly impaired, based on the assessment of the formation of RAD51 foci by microscopy and of the biochemical analysis of RAD51 accumulation on chromatin. Although the mechanism by which TOP BP1 promotes the loading of RAD51 remains unclear, the authors propose an interesting model in which TOP BP1 plays a scaffolding role to direct Polo-like Kinase 1 (PLK1), which phosphorylates RAD51 and facilitates its loading to DNA damage sites (Fig. 1 A; Yata et al., 2012). Consistent with this model, they show that TOP BP1 physically interacts with...

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The Caenorhabditis elegans WRN helicase promotes double‐strand DNA break repair by mediating end resection and checkpoint activation

Ryu

Koo

2017

FEBS Letters

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The protein associated with Werner syndrome (WRN), is involved in DNA repair, checkpoint activation, and telomere maintenance. To better understand the involvement of WRN in double-strand DNA break (DSB) repair, we analyzed the combinatorial role of WRN-1, the Caenorhabditis elegans WRN helicase, in conjunction with EXO-1 and DNA-2 nucleases. We found that WRN-1 cooperates with DNA-2 to resect DSB ends in a pathway acting in parallel to EXO-1. The wrn-1 mutants show an aberrant accumulation of replication protein A (RPA) and RAD-51, and the same pattern of accumulation is also observed in checkpoint-defective strains. We conclude that WRN-1 plays a conserved role in the resection of DSB ends and mediates checkpoint signaling, thereby influencing levels of RPA and RAD-51.

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TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

Abstract: TOPBP1 acts in homologous recombination repair, impacts the response to chemotherapeutic agent olaparib, and exhibits aberrant patterns in subsets of human ovarian carcinomas.

Cited by 76 publications

References 29 publications

Multi-BRCT scaffolds use distinct strategies to support genome maintenance

Multi-BRCT scaffolds use distinct strategies to support genome maintenance

TOPBP1 takes RADical command in recombinational DNA repair

The Caenorhabditis elegans WRN helicase promotes double‐strand DNA break repair by mediating end resection and checkpoint activation

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