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WIP1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation

ABSTRACT: WIP1 phosphatase is emerging as an important regulator of tumorigenesis, but no unifying mechanistic network has been proposed. Here we found that WIP1 plays a key role in the transcriptional regulation of heterochromatin-associated DNA sequences in germ-line and cancer cells. WIP1 was required for epigenetic remodeling of repetitive DNA elements within the heterochromatin, including L1 LINE retrotransposons. Mechanistically, WIP1regulated an ATM-dependent increase in BRCA1 occupancy on L1 LINEs, resulting in closed chromatin without ubiquitination of histone H2A. This mechanism appeared to be dependent on the ability of BRCA1 to bind the heterochromatin protein HP1, the recruitment of DNA methyltransferases, and subsequent DNA methylation. Attenuation of ATM, in turn, reversed heterochromatin methylation in both germ-line and cancer cells. DNA methylation plays a central role in the generation of mutations in human tumors and we found that WIP1 levels strongly correlated with C-to-T substitutions and a total mutation load in primary breast cancers. We propose that WIP1 plays an important role in the regulation of DNA methylation and global heterochromatin silencing, and thus is critical in maintaining genome integrity during development and in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE46103 | GEO | 2013/10/19

SECONDARY ACCESSION(S): PRJNA197260

REPOSITORIES: GEO

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WIP1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation

Project description:WIP1 phosphatase is emerging as an important regulator of tumorigenesis, but no unifying mechanistic network has been proposed. Here we found that WIP1 plays a key role in the transcriptional regulation of heterochromatin-associated DNA sequences in germ-line and cancer cells. WIP1 was required for epigenetic remodeling of repetitive DNA elements within the heterochromatin, including L1 LINE retrotransposons. Mechanistically, WIP1regulated an ATM-dependent increase in BRCA1 occupancy on L1 LINEs, resulting in closed chromatin without ubiquitination of histone H2A. This mechanism appeared to be dependent on the ability of BRCA1 to bind the heterochromatin protein HP1, the recruitment of DNA methyltransferases, and subsequent DNA methylation. Attenuation of ATM, in turn, reversed heterochromatin methylation in both germ-line and cancer cells. DNA methylation plays a central role in the generation of mutations in human tumors and we found that WIP1 levels strongly correlated with C-to-T substitutions and a total mutation load in primary breast cancers. We propose that WIP1 plays an important role in the regulation of DNA methylation and global heterochromatin silencing, and thus is critical in maintaining genome integrity during development and in cancer. Total RNA was extracted from control spermatids, Wip1-/- and Wip1-/- Atm+/- spermatids. The final cRNA samples were hybridized in triplicates to Illumina Mouse WG-6 v2.0 Expression arrays.

2013-10-19 | E-GEOD-46103 | biostudies-arrayexpress

Mus musculus

Project description:WIP1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation

| PRJNA197260 | ENA

LINE-1 RNA is causative of heterochromatin erosion and target for amelioration of senescent phenotypes in progeroid syndromes

2022-11-02 | PXD032944 | Pride

Jaiswal2017 - Cell cycle arrest

Project description:Jaiswal2017 - Cell cycle arrest This model is described in the article: ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration. Jaiswal H, Benada J, Müllers E, Akopyan K, Burdova K, Koolmeister T, Helleday T, Medema RH, Macurek L, Lindqvist A. EMBO J. 2017 Jul; 36(14): 2161-2176 Abstract: After DNA damage, the cell cycle is arrested to avoid propagation of mutations. Arrest in G2 phase is initiated by ATM-/ATR-dependent signaling that inhibits mitosis-promoting kinases such as Plk1. At the same time, Plk1 can counteract ATR-dependent signaling and is required for eventual resumption of the cell cycle. However, what determines when Plk1 activity can resume remains unclear. Here, we use FRET-based reporters to show that a global spread of ATM activity on chromatin and phosphorylation of ATM targets including KAP1 control Plk1 re-activation. These phosphorylations are rapidly counteracted by the chromatin-bound phosphatase Wip1, allowing cell cycle restart despite persistent ATM activity present at DNA lesions. Combining experimental data and mathematical modeling, we propose a model for how the minimal duration of cell cycle arrest is controlled. Our model shows how cell cycle restart can occur before completion of DNA repair and suggests a mechanism for checkpoint adaptation in human cells. This model is hosted on BioModels Database and identified by: BIOMD0000000641. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

2014-03-28 | BIOMD0000000641 | BioModels

LINE-1 antisense oligonucleotide ameliorate HGPA and WRN aging phenotype.

Project description:Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. L1 RNA negatively regulates Suv39H1 enzymatic activity, resulting in heterochromatin loss and onset of senescent phenotypes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, preserves DNA methylation and counteracts the expression of senescence-associated genes. Moreover, systemic delivery of ASO rescues the histophysiology of all tissues and increases the lifespan of Hutchinson-Gilford Progeria Syndrome (HGPS) mouse model. Furthermore, the transcriptional profiling following L1 RNA depletion shows that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response and DNA damage were downregulated. Our results show a key role of L1 RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.

2022-08-24 | GSE198675 | GEO

Substrate spectrum of PPM1D in the cellular response to DNA double strand breaks

Project description:PPM1D (also known as WIP1) is a p53-regulated protein phosphatase that modulates the DNA damage response (DDR) by dephosphorylation of DDR proteins. Amplification of PPM1D gene or gain-of-function mutations are commonly found in cancer. Here, we employed chemical inhibition of PPM1D and quantitative mass spectrometry-based phosphoproteomics to identify the substrates of PPM1D upon induction of DNA double strand breaks (DSBs) by topoisomerase II poison etoposide. We identified 73 putative PPM1D substrates that are involved in DNA repair, regulation of transcription and RNA processing. One third of DSB-induced S/TQ phosphorylation sites are dephosphorylated by PPM1D, demonstrating that PPM1D only partially counteracts ATM/ATR/DNA-PK signaling. PPM1D-targeted phosphorylation sites are found in a specific amino acid sequence motif that is characterized by glutamic acid residues, high intrinsic disorder and poor evolutionary conservation. We identified a functionally uncharacterized protein Kanadaptin as ATM and PPM1D substrate upon DSB induction. We propose that PPM1D plays a role during the response to DSBs formation by regulating the phosphorylation of DNA- and RNA-binding proteins in intrinsically disordered regions.

2022-09-06 | PXD035420 | Pride

Genome-wide DNA methylation mapping in preadipocytes

Project description:DNA methylation plays a crucial role in the regulation of gene transcription. In this study, using MeDIP-seq experiment, we report the mapping of DNA methylation in undifferentiated 3T3-L1 cells (preadipocytes). Examination of DNA methylation pattern in undifferentiated 3T3-L1 cells (preadipocytes)

2013-11-29 | E-GEOD-50992 | biostudies-arrayexpress

ATM Loss and Therapeutic Vulnerabilities in Bladder Cancer

Project description:ATM plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations in bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair targeted agents including PARP and ATR inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Finally, we show that ATM expression by IHC is strongly correlated with response to chemoradiotherapy. Together these data define a potential role for ATM as a predictive biomarker in bladder cancer.

2023-11-24 | GSE232850 | GEO

ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks

Project description:Mutations in the ATM tumor suppressor gene confer cellular hypersensitivity to various DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms towards such drugs, we performed genome-wide CRISPR-Cas9 loss-of-function screens in cells treated with the DNA topoisomerase I poison topotecan. Our ensuing characterizations of hits established that loss of terminal components of the non-homologous end joining (NHEJ) machinery or components of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. Our findings indicate that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib is due to delayed engagement of homologous recombination repair (HRR) at a subset of DNA-replication-fork associated single ended double-strand breaks (seDSBs), which allows non-homologous end joining (NHEJ) mediated repair, resulting in toxic chromosome fusions. Thus, restoration of legitimate repair in ATM-deficient cells – either by preventing the DNA ligation step of NHEJ or by enhancing HRR engagement by deregulating the BRCA1-A complex – markedly suppresses this toxicity. We conclude that the crucial role for ATM at seDSBs is to prevent toxic LIG4-mediated NHEJ at damaged replication forks. Furthermore, our observation that suppressor mutations in ATM-mutant backgrounds are fundamentally different to those that operate in BRCA1-mutant scenarios suggests new opportunities for patient stratification in the clinic, as well as additional therapeutic vulnerabilities that might be exploited in drug-resistant cancers.

2019-11-12 | PXD011108 | Pride

LSD1 Prevents Aberrant Heterochromatin Formation in Neurospora crassa

Project description:Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. Here we explore whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1, and strains deficient for any exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains dispersed across the genome. Heterochromatin establishment outside of canonical domains in Neurospora share the unusual characteristic of DNA methylation-dependent H3K9me3; typically, H3K9me3 establishment is independent of DNA methylation. Consistent with this, the hyper-H3K9me3 phenotype of LSD1 knock-out strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.

2021-07-21 | PXD017300 | Pride

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