Investigation of the biological and molecular functions of the CpG island-binding protein SAMD1
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Abstract
The protein SAMD1 is a transcriptional repressor with a crucial role in development. It binds to unmethylated, CpG-rich promoters and mediates transcriptional repression of genes involved in a multitude of cellular pathways. SAMD1 contains two ordered domains, an N-terminal DNA-binding winged helix domain and a C-terminal polymerising sterile alpha motif domain, as well as an intrinsically disordered region in between.
The first part of this work aims at elucidating the mechanisms involved in SAMD1 chromatin binding. Both ordered domains are required but not sufficient for chromatin binding, suggesting the involvement of an unknown third component.
Upon detailed biochemical analysis, we have identified a distinct part of SAMD1’s intrinsically disordered region which is essential for both chromatin binding and protein polymerisation. Additionally, we identified several arginine residues within the disordered region, which are crucial for SAMD1’s function. Their mutation to alanine impairs both protein polymerisation and chromatin binding; and ultimately prevents SAMD1 from fulfilling its biological function in cell culture models.
Multi-faceted functions render SAMD1 an important player in various diseases, including cancer. While SAMD1 has been shown to play a pro-tumourigenic role in hepatocellular carcinoma, patient data from pancreatic adenocarcinoma points towards a tumour suppressive role.
The second part of this work strives to characterise the role of SAMD1 in pancreatic ductal adenocarcinoma to gain a better understanding of its the intricate role in cancer.
Our work identified SAMD1 as negative regulator of pathways related to epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma. SAMD1 limits migration and invasion capacity in cell culture models, mainly via transcriptional repression of the CDH2 gene.
Overall, we gained further insights into SAMD1 function via identification of chromatin binding modules and characterisation of its role in pancreatic cancer.
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Issued: 2026-03-10
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Other relations: (DOI) 10.1093/nar/gkaf259Other relations: (DOI) 10.1371/journal.pbio.3002739
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FB20:Medizin
Language
en
Keywords
ChromatinSAMD1PDAC
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Geller, Merle: Investigation of the biological and molecular functions of the CpG island-binding protein SAMD1. : 2026-03-10. DOI: https://doi.org/10.17192/openumr/567.
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Except where otherwised noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International