ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice

Batenburg, Nicole L.; Walker, John R.; Noordermeer, Sylvie M.; Moatti, Nathalie; Durocher, Daniel; Zhu, Xu-Dong

doi:10.1038/s41467-017-02114-x

Cited by 58 publications

(103 citation statements)

References 63 publications

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“…We observed that, despite the relative increase in H2AK119Ub1 levels ( Figure 3A–C ), H2A levels were significantly reduced at the FokI nuclease-induced DNA damage sites ( Figure 6—figure supplement 1A ), in agreement with previous reports ( Batenburg et al, 2017 ; Berkovich et al, 2007 ; Strickfaden et al, 2016 ). Importantly, this reduction was inhibited by the depletion of FBXL10, RNF68, or RNF2, suggesting that the FRRUC is involved in the eviction of H2A near DNA damage sites ( Figure 6—figure supplement 1A ).…”

Section: Resultssupporting

confidence: 93%

PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading

Róna

Roberti

Yin

et al. 2018

eLife

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The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono-ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR.

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Section: Resultssupporting

confidence: 93%

PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading

Róna

Roberti

Yin

et al. 2018

eLife

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“…When the paper was under revision, the study by Batenburg et al , showing that ATM and CDK2 control the chromatin remodeling activity of CSB in the regulation of DSB repair pathway choice, was published in Nature Communications [ 61 ].…”

Section: Methodsmentioning

confidence: 99%

CSA and CSB play a role in the response to DNA breaks

Pascucci¹,

Fragale

Marabitti

et al. 2018

Oncotarget

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CS proteins have been involved in the repair of a wide variety of DNA lesions. Here, we analyse the role of CS proteins in DNA break repair by studying histone H2AX phosphorylation in different cell cycle phases and DNA break repair by comet assay in CS-A and CS-B primary and transformed cells. Following methyl methane sulphate treatment a significant accumulation of unrepaired single strand breaks was detected in CS cells as compared to normal cells, leading to accumulation of double strand breaks in S and G2 phases. A delay in DSBs repair and accumulation in S and G2 phases were also observed following IR exposure. These data confirm the role of CSB in the suppression of NHEJ in S and G2 phase cells and extend this function to CSA. However, the repair kinetics of double strand breaks showed unique features for CS-A and CS-B cells suggesting that these proteins may act at different times along DNA break repair.The involvement of CS proteins in the repair of DNA breaks may play an important role in the clinical features of CS patients.

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“…56 Additionally, as a member of the SWI2/ SNF2 superfamily, CBS could be phosphorylated by ATM and CDK2, which may regulate CBS chromatin remodeling activity involved in the DNA double-strand break (DSB) repair pathway. 57 Furthermore, the acetyltransferase PCAF could acetylate mammalian BRM to negatively impact BRM activities as a chromatin remodeler, including transcriptional activation as well as growth modulation. 58 However, the methylation of chromatin remodelers alone has been infrequently reported, especially arginine methylation.…”

Section: Discussionmentioning

confidence: 99%

The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties

Liu

Yang

Shi

et al. 2020

Sig Transduct Target Ther

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Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we demonstrate that LSH is capable to undergo PTMs, including methylation and phosphorylation. The arginine methyltransferase PRMT5 can methylate LSH at R309 residue, meanwhile, LSH could as well be phosphorylated by MAPK1 kinase at S503 residue. We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue, which eventually promoting stem-like properties in lung cancer. Whereas, phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties, indicating the critical roles of LSH PTMs in modulating stem-like properties. Thus, our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.

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ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice

Cited by 58 publications

References 63 publications

PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading

PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading

CSA and CSB play a role in the response to DNA breaks

The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties

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