Targeting of the Fun30 nucleosome remodeller by the Dpb11 scaffold facilitates cell cycle-regulated DNA end resection

Bantele, Susanne C. S.; Ferreira, Pedro; Gritenaite, Dalia; Boos, Dominik; Pfander, Boris

doi:10.7554/elife.21687

Cited by 51 publications

(112 citation statements)

References 62 publications

(116 reference statements)

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“…Consistent with the recruitment of Fun30 to DSBs, SMARCAD1 was also found to be recruited to laser-induced DNA damage sites and nuclease-induced DSBs, where γH2AX is co-localised [12]. More recently, the functions of Fun30 as a target of CDK phosphorylation [10,11,14] and SMARCAD1 at DSBs are found to be cell cycle regulated [15,16]. All these data suggest an evolutionarily conserved role for the Fun30 and SMARCAD1 chromatin remodelers.…”

Section: Introductionsupporting

confidence: 59%

SMARCAD1 in Breast Cancer Progression

Arafat

Kubaisy

Sulaiman

et al. 2018

Cell Physiol Biochem

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Background/Aims: Breast cancer is the most common cancer in women worldwide, and within this cancer type, triple-negative breast cancers have the worst prognosis. The identification of new genes associated with triple-negative breast cancer progression is crucial for developing more specific anti-cancer targeted therapies, which could lead to a better management of these patients. In this context, we have recently demonstrated that SMARCAD1, a DEAD/H box-containing helicase, is involved in breast cancer cell migration, invasion, and metastasis. The aim of this study was to investigate the impact of the stable knockdown of SMARCAD1 on human breast cancer cell progression. Methods: Using two different designs of shRNA targeting SMARCAD1, we investigated the impact of the stable knockdown of SMARCAD1 on human breast cancer cell proliferation and colony growth in vitro and on tumour growth in chick embryo and nude mouse xenograft models in vivo using MDA-MB-231 (ER^-/PR^-/ HER2^-) and T47D (ER⁺/PR^+/-/HER2^-) human breast cancer cell lines. Results: We found that SMARCAD1 knockdown resulted in a significant decrease in breast cancer cell proliferation and colony formation, leading to the significant inhibition of tumour growth in both the chick embryo and nude mouse xenograft models. This inhibition was due, at least in part, to a decrease in IKKβ expression. Conclusion: These results indicate that SMARCAD1 is involved in breast cancer progression and can be a promising target for breast cancer therapy.

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Section: Introductionsupporting

confidence: 59%

SMARCAD1 in Breast Cancer Progression

Arafat

Kubaisy

Sulaiman

et al. 2018

Cell Physiol Biochem

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“…Residual Rad9 binding to chromatin is observed in mutants deficient for 9-1-1 resulting in only partial de-repression of resection at DSBs (57,63). The positive function of 9-1-1 in resection is through recruitment of the Fun30 SMARCAD1 chromatin remodeler (64), which counteracts the negative effect of Rad9 on resection (40, 41, 64, 65). In addition, Slx4-Rtt107 competes with Rad9 for binding to γH2A and to Dpb11.…”

Section: Discussionmentioning

confidence: 99%

“…Human EXO1 is also activated for end resection by CDK (68). The other positive action of CDK is by phosphorylation of Fun30 and Slx4, which is required for their interaction with Dpb11, and hence to 9-1-1 at the recessed 5' end (47, 64,69). While Mec1 and Tel1-mediated phosphorylation of Sae2 is important for resection (70), Mec1 and Tel1 act to repress extensive resection via recruitment of Rad9 and Rad53 to DSBs (71).…”

Section: Discussionmentioning

confidence: 99%

Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection

Kimble

2018

Preprint

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The Mre11-Rad50-Xrs2 NBS1 complex plays important roles in the DNA damage response by activating the Tel1 ATM kinase and catalyzing 5'-3' resection at DNA double-strand breaks (DSBs). To initiate resection, Mre11 endonuclease nicks the 5' strands at DSB ends in a reaction stimulated by Sae2 CtIP . Accordingly, Mre11-nuclease deficient (mre11nd) and sae2Δ mutants are expected to exhibit similar phenotypes; however, we found several notable differences. First, sae2Δ cells exhibit greater sensitivity to genotoxins than mre11-nd cells. Second, sae2Δ is synthetic lethal with sgs1Δ, whereas the mre11nd sgs1Δ mutant is viable. Third, Sae2 attenuates the Tel1-Rad53 CHK2 checkpoint and antagonizes Rad9 53BP1 accumulation at DSBs independent of Mre11 nuclease. We show that Sae2 competes with other Tel1 substrates, thus reducing Rad9 binding to chromatin and to Rad53. We suggest that persistent Sae2 binding at DSBs in the mre11-nd mutant counteracts the inhibitory effects of Rad9 and Rad53 on Exo1 and Dna2-Sgs1 mediated resection, accounting for the different phenotypes conferred by mre11-nd and sae2Δ mutations. Collectively, these data show a resection initiation independent role for Sae2 at DSBs by modulating the DNA damage checkpoint.

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“…Consequently, a number of nucleosome remodeling factors have been linked to HR (Chai et al, 2005;Kalocsay et al, 2009;Morrison et al, 2004;Shim et al, 2007). One of the best documented examples in this regard is Fun30 (human SMARCAD1), which is critical for the extended generation of ssDNA during DNA end resection (Bantele et al, 2017;Chen et al, 2012Chen et al, , 2016Costelloe et al, 2012;Eapen et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The INO80 Complex Removes H2A.Z to Promote Presynaptic Filament Formation during Homologous Recombination

et al. 2017

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The INO80 complex (INO80-C) is an evolutionarily conserved nucleosome remodeler that acts in transcription, replication, and genome stability. It is required for resistance against genotoxic agents and is involved in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). However, the causes of the HR defect in INO80-C mutant cells are controversial. Here, we unite previous findings using a system to study HR with high spatial resolution in budding yeast. We find that INO80-C has at least two distinct functions during HR-DNA end resection and presynaptic filament formation. Importantly, the second function is linked to the histone variant H2A.Z. In the absence of H2A.Z, presynaptic filament formation and HR are restored in INO80-C-deficient mutants, suggesting that presynaptic filament formation is the crucial INO80-C function during HR.

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Targeting of the Fun30 nucleosome remodeller by the Dpb11 scaffold facilitates cell cycle-regulated DNA end resection

Cited by 51 publications

References 62 publications

SMARCAD1 in Breast Cancer Progression

SMARCAD1 in Breast Cancer Progression

Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection

The INO80 Complex Removes H2A.Z to Promote Presynaptic Filament Formation during Homologous Recombination

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