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HMGB1 Protein Interactions in Prostate and Ovary Cancer Models Reveal Links to RNA Processing and Ribosome Biogenesis through NuRD, THOC and Septin Complexes.

ABSTRACT: This study reports the HMGB1 interactomes in prostate and ovary cancer cells lines. Affinity purification coupled to mass spectrometry confirmed that the HMGB1 nuclear interactome is involved in HMGB1 known functions such as maintenance of chromatin stability and regulation of transcription, and also in not as yet reported processes such as mRNA and rRNA processing. We have identified an interaction between HMGB1 and the NuRD complex and validated this by yeast-two-hybrid, confirming that the RBBP7 subunit directly interacts with HMGB1. In addition, we describe for the first time an interaction between two HMGB1 interacting complexes, the septin and THOC complexes, as well as an interaction of these two complexes with Rab11. Analysis of Pan-Cancer Atlas public data indicated that several genes encoding HMGB1-interacting proteins identified in this study are dysregulated in tumours from patients diagnosed with ovary and prostate carcinomas. In PC-3 cells, silencing of HMGB1 leads to downregulation of the expression of key regulators of ribosome biogenesis and RNA processing, namely BOP1, RSS1, UBF1, KRR1 and LYAR. Upregulation of these genes in prostate adenocarcinomas is correlated with worse prognosis, reinforcing their functional significance in cancer progression.

SUBMITTER: Barreiro-Alonso A

PROVIDER: S-EPMC8466577 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:All classes of RNA undergo processing. The two largest RNA processing complexes are those involved in rRNA biogenesis and mRNA splicing. Because of their complexity and essential roles, it has been difficult to dissect the functional interactions within these machines as well as to identify possible cross-talk with other steps in gene expression. Here we report the results of a high-density, quantitative genetic interaction map comprising 107,155 individual interactions involving 552 mutants, 166 of which are hypomorphic alleles of essential genes (This data is available at The Krogan Lab Interactome Database). Our data allow unique insights into the functional organization of the RNA processing machines. For example, we identify unexpected connections involving a component of the 19S proteasome, Sem1/Dss1. We show that Sem1 has genetic, physical and functional interactions with the mRNA export complex, Thp1-Sac3; it also interacts physically with a putative component of the COP9 signalosome, Csn12. We show using splicing-specific microarrays that Csn12 has an unanticipated role in mRNA splicing. Finally, we demonstrate the utility of this dataset in determining functions for uncharacterized ORFs. We show that deletion of the uncharacterized YNR004W causes a very similar splicing defect to that caused by deletion of TGS1, the enzyme that trimethylates the caps of snRNAs and snoRNAs. Keywords: E-MAP, RNA Processing, splicing, splicing-specific microarray, CSN12, COP9 signalosome Splicing-specific microarrays were used to assay the changes to splicing caused by deletion of several non-essential genes which had no previously characterized role in mRNA splicing but were suggested to be involved in this process by high-throughput genetic and/or protein-protein interaction data in Saccharomyces cerevisiae. The data includes samples collected from some mutants in log phase growth at 30 degrees C and from some mutants shifted to 16 degrees C, all competitively hybridized against wild type samples collected under the same conditions. .

Dataset Information

HMGB1 Protein Interactions in Prostate and Ovary Cancer Models Reveal Links to RNA Processing and Ribosome Biogenesis through NuRD, THOC and Septin Complexes.

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