A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair

Li, Weizhe; Wang, Hongyan; Zhao, Xiaolu; Duan, Hongguo; Cheng, Binghua; Liu, Yafei; Zhao, Mengjie; Shu, Wen-Jie; Mei, Yuchao; Wen, Zengqi; Tang, Mingliang; Guo, Lin; Li, Guohong; Chen, Qiang; Liu, Xiaoqi; Du, Hai-Ning

doi:10.1126/sciadv.aau7566

Cited by 62 publications

(51 citation statements)

References 42 publications

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“…One study showed that SETD6 methylates PLK1 at K209 and K413 which keep mitosis in check and deficiency of SETD6 activity promotes cellular proliferation ( Feldman et al, 2019 ). The second study described that PLK1 activity is controlled by methyltransferase G9a at Lys209 ( Li et al, 2019 ), which antagonizes phosphorylation of T210 to inhibit PLK1 activity, and all these three sites are labelled in Supplementary Figure S3B . Since the methyl-deficient mutant K209A affects DNA replication, it is likely that Lys209 methylation is a switch for PLK1 function in DNA damage repair.…”

Section: Discussionmentioning

confidence: 99%

Methylation of PLK1 by SET7/9 ensures accurate kinetochore–microtubule dynamics

Ismail

et al. 2019

Journal of Molecular Cell Biology

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Abstract Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying PLK1 activation have been extensively studied, the regulatory mechanisms that couple PLK1 activity to accurate chromosome segregation are not well understood. In particular, PLK1 is implicated in stabilizing kinetochore–microtubule attachments, but how kinetochore PLK1 activity is regulated to avoid hyperstabilized kinetochore–microtubules in mitosis remains elusive. Here, we show that kinetochore PLK1 kinase activity is modulated by SET7/9 via lysine methylation during early mitosis. The SET7/9-elicited dimethylation occurs at the Lys191 of PLK1, which tunes down its activity by limiting ATP utilization. Overexpression of the non-methylatable PLK1 mutant or chemical inhibition of SET7/9 methyltransferase activity resulted in mitotic arrest due to destabilized kinetochore–microtubule attachments. These data suggest that kinetochore PLK1 is essential for stable kinetochore–microtubule attachments and methylation by SET7/9 promotes dynamic kinetochore–microtubule attachments for accurate error correction. Our findings define a novel homeostatic regulation at the kinetochore that integrates protein phosphorylation and methylation with accurate chromosome segregation for maintenance of genomic stability.

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Section: Discussionmentioning

confidence: 99%

Methylation of PLK1 by SET7/9 ensures accurate kinetochore–microtubule dynamics

Ismail

et al. 2019

Journal of Molecular Cell Biology

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“…Current models suggest that ATR/CHK1 postpones the activation of CDK1 through Cdc25/Wee1 regulation, similar to the response to DNA damage (Goto et al, 2019;Sørensen and Syljuåsen, 2012). How PLK1 is suppressed during unperturbed proliferation is not clear, but after DNA damage, PLK1 activity is limited by dephosphorylation, disruption of Aurora A-Bora interaction, and direct methylation (Bruinsma et al, 2017;Hu et al, 2018;Li et al, 2019). In addition, PLK1 and CDK1 activity are tightly interlinked, and suppression of one can affect the other (Gheghiani et al, 2017;Lindqvist et al, 2009;Macůrek et al, 2008;Seki et al, 2008;Thomas et al, 2016;Vigneron et al, 2018).…”

Section: G1/s Brakementioning

confidence: 99%

DNA replication and mitotic entry: A brake model for cell cycle progression

Lemmens

Lindqvist

2019

Journal of Cell Biology

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The core function of the cell cycle is to duplicate the genome and divide the duplicated DNA into two daughter cells. These processes need to be carefully coordinated, as cell division before DNA replication is complete leads to genome instability and cell death. Recent observations show that DNA replication, far from being only a consequence of cell cycle progression, plays a key role in coordinating cell cycle activities. DNA replication, through checkpoint kinase signaling, restricts the activity of cyclin-dependent kinases (CDKs) that promote cell division. The S/G2 transition is therefore emerging as a crucial regulatory step to determine the timing of mitosis. Here we discuss recent observations that redefine the coupling between DNA replication and cell division and incorporate these insights into an updated cell cycle model for human cells. We propose a cell cycle model based on a single trigger and sequential releases of three molecular brakes that determine the kinetics of CDK activation.

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“…As p38 is the primary effector of MKK3 signaling in response to cellular stress and cytokine stimulation(29), as well as chromatin conformational changes such as those observed in Figure 2, we hypothesized that DNA methylation also regulates p38 expression in CNFs and PNFs. Because methylation events can also impact kinase activation(30), we also assessed whether MAP2K3 methylation events affected downstream P38 activation. We identified a significant DMR (p = 1.66E-16) approximately 3.5 kb upstream of the MAPK14 gene, which encodes the p38α isoform.…”

Section: Resultsmentioning

confidence: 99%

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/P38 signaling

Grit

Johnson

Essenburg

et al. 2019

Preprint

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Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity in NF1 and are difficult to manage. Cutaneous (CNF) and plexiform neurofibromas (PNF) share identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for their disparate clinical behavior are not well explained on the basis of recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs (Illumina EPIC 850K) using normal tissue controls from NF1 subjects. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher order chromatin states, and specific methylation events altering genes involved in key biological and cellular processes such as inflammatory mediator regulation of TRP channels, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling.Based our identification of 2 separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/P38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/P38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/ERK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that epigenetic regulation of RAS signaling fates accounts for observed differences in CNF and PNF clinical behavior. CNFs may also respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting P38mediated inflammation for CNF treatment.Copy number estimation from EPIC methylation arrays Copy number alterations were computed using SeSAMe (v1.3.2) with minor modifications for plotting functionality. Briefly, data were processed using the "open SeSAMe" procedure, producing a signal set object. Next, samples were segmented and called for copy number differences, comparing CNFs to normal skin and PNFs to normal nerve. The genome annotation used was hg19. RNA-sequencing data analysis

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A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair

Cited by 62 publications

References 42 publications

Methylation of PLK1 by SET7/9 ensures accurate kinetochore–microtubule dynamics

Methylation of PLK1 by SET7/9 ensures accurate kinetochore–microtubule dynamics

DNA replication and mitotic entry: A brake model for cell cycle progression

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/P38 signaling

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