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

Gräf, Justus F.; Mikičić, Ivan; Ping, Xiaofei; Scalera, Claudia; Mayr, Katharina; Stelzl, Lukas S.; Beli, Petra; Wagner, Sebastian

doi:10.1016/j.isci.2022.104892

Cited by 7 publications

(7 citation statements)

References 101 publications

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“…The 7 CpG sites identified in this study were associated with five genes: PPM1D, PANX1, ENDOD1, MAF, and MYH2. PPM1D is a tumor suppressor gene and has been associated with various types of cancer, including breast, ovarian, and colorectal cancer; mutations of this gene may impact the ability of the body to repair damaged DNA 33 . PANX1 encodes a protein involved in intercellular communication, and mutations of this gene are associated with an increased expression of molecules involved in cancer growth 34 .…”

Section: Discussionmentioning

confidence: 99%

A novel DNA methylation signature to improve survival prediction of progression-free survival for testicular germ cell tumors

Gao

Jiang

et al. 2023

Sci Rep

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This study aimed to develop a nomogram for predicting the progression-free survival (PFS) of testicular germ cell tumors (TGCT) patients based on DNA methylation signature and clinicopathological characteristics. The DNA methylation profiles, transcriptome data, and clinical information of TGCT patients were obtained from the Cancer Genome Atlas (TCGA) database. Univariate Cox, lasso Cox, and stepwise multivariate Cox regression were applied to identify a prognostic CpG sites-derived risk signature. Differential expression analysis, functional enrichment analysis, immunoinfiltration analysis, chemotherapy sensitivity analysis, and clinical feature correlation analysis were performed to elucidate the differences among risk groups. A prognostic nomogram integrating CpG sites-derived risk signature and clinicopathological features was further established and evaluated likewise. A risk score model based on 7 CpG sites was developed and found to exhibit significant differences among different survival, staging, radiotherapy, and chemotherapy subgroups. There were 1452 differentially expressed genes between the high- and low-risk groups, with 666 being higher expressed and 786 being lower expressed. Genes highly expressed were significantly enriched in immune-related biological processes and related to T-cell differentiation pathways; meanwhile, down-regulated genes were significantly enriched in extracellular matrix tissue organization-related biological processes and involved in multiple signaling pathways such as PI3K-AKT. As compared with the low-risk group, patients in the high-risk group had decreased lymphocyte infiltration (including T-cell and B-cell) and increased macrophage infiltration (M2 macrophages). They also showed decreased sensitivity to etoposide and bleomycin chemotherapy. Three clusters were obtained by consensus clustering analysis based on the 7 CpG sites and showed distinct prognostic features, and the risk scores in each cluster were significantly different. Multivariate Cox regression analysis found that the risk scores, age, chemotherapy, and staging were independent prognostic factors of PFS of TGCT, and the results were used to formulate a nomogram model that was validated to have a C-index of 0.812. Decision curve analysis showed that the nomogram model was superior to other strategies in the prediction of PFS of TGCT. In this study, we successfully established CpG sites-derived risk signature, which might serve as a useful tool in the prediction of PFS, immunoinfiltration, and chemotherapy sensitivity for TGCT patients.

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Section: Discussionmentioning

confidence: 99%

A novel DNA methylation signature to improve survival prediction of progression-free survival for testicular germ cell tumors

Gao

Jiang

et al. 2023

Sci Rep

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“…PPM1D is noted to be missense constrained but not loss‐of‐function constrained in the gnomAD database, which fits with the finding that the mechanism of disease in for JdVS entails escape from nonsense‐mediated decay (Coban‐Akdemir et al, 2018). PPM1D is known to be a negative regulator of p53 and other tumor suppressors, and somatic variants are found in multiple malignancies (Graf et al, 2022; Khadka et al, 2022). There are several individuals with stop gain variants designated as ClinVar pathogenic/likely pathogenic in gnomAD, though at least one is present in an older individual; these may represent somatic variants acquired in the setting of clonal hematopoiesis of indeterminate potential, as has been reported with this gene, particularly in association with myelodysplastic syndromes (Panagiota et al, 2021; Zink et al, 2017) and has been previously seen in other highly penetrant, autosomal dominant conditions (Carlston et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Wojcik

Srivastava

Agrawal

et al. 2023

American J of Med Genetics Pt A

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Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

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“…Of the 21 subjects, five were diagnosed with autism spectrum disorder (ASD) before their deterioration that met PANS criteria. In addition to ASD, four cases were diagnosed with another neurodevelopmental disorder (NDD), one of whom had Jansen de Vries Syndrome (JdVS), which is caused by truncating mutations in PPM1D exons 5 or 6 that cause a gain-of-function effect by suppressing p53 and other proteins involved in the DNA damage repair response (DDR) (e.g., MDM2, ATM, CHK1, CHK2, ATR, and H2AX) [2][3][4][5][6] . The high prevalence of PANS superimposed on pre-existing NDD is consistent with the observations of other groups 7,8 .…”

Section: Introductionmentioning

confidence: 99%

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

Cunningham,

Frankovich,

Dubin

et al. 2024

Preprint

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Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR):PPM1D, CHK2,andRAG1. We now report an additional 17 cases with mutations inPPM1Dand other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that were classified by their clinicians as PANS or another inflammatory brain condition. The genes include clusters affecting p53 DNA repair (PPM1D,ATM, ATR,53BP1,andRMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI,andFANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could lead to an increase in cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes. These findings could lead to new treatment strategies.

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

Cited by 7 publications

References 101 publications

A novel DNA methylation signature to improve survival prediction of progression-free survival for testicular germ cell tumors

A novel DNA methylation signature to improve survival prediction of progression-free survival for testicular germ cell tumors

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

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