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The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

ABSTRACT: Men with melanoma have a significantly worse prognosis than women, and the biological underpinnings of this difference are unknown. The current study demonstrates that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis free survival. High expression of the gonosomal PPP2R3B gene, a gene that escapes inactivation, is independently correlated with survival. PPP2R3B downregulates melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6/CDT1 interaction during the replication origins firing and as such behaves functionally as a tumor suppressor gene.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66839 | GEO | 2016/08/01

SECONDARY ACCESSION(S): PRJNA278070

REPOSITORIES: GEO

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The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

Project description:Men with melanoma have a significantly worse prognosis than women, and the biological underpinnings of this difference are unknown. The current study demonstrates that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis free survival. High expression of the gonosomal PPP2R3B gene, a gene that escapes inactivation, is independently correlated with survival. PPP2R3B downregulates melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6/CDT1 interaction during the replication origins firing and as such behaves functionally as a tumor suppressor gene. Fourty-nine fresh frozen primary melanoma samples were profiled by CGH array using sex-matched commercial DNA as reference.

2016-08-01 | E-GEOD-66839 | biostudies-arrayexpress

Comparative genomic hybridization of S. pombe co-overexpressing DNA synthesis initiation factors cdc18 (cdc6) and cdt1 to investigate gene copy number increases

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Single stranded DNA formation during S phase in orc4Y232C yeast cells

Project description:A form of dwarfism known as Meier-Gorlin syndrome (MGS) is caused by recessive mutations in one of six different genes (ORC1, ORC4, ORC6, CDC6, CDT1, and MCM5). These genes encode components of the pre-replication complex, which assembles at origins of replication prior to S phase. Also, variants in two additional replication initiation genes have joined the list of causative mutations for MGS (Geminin and CDC45). The identity of the causative MGS genetic variants strongly suggests that some aspect of replication is amiss in MGS patients; however, little evidence has been obtained regarding what aspect of chromosome replication is faulty. Since the site of one of the missense mutations in the human ORC4 alleles is conserved between humans and yeast, we sought to determine in what way this single amino acid change affects the process of chromosome replication, by introducing the comparable mutation into yeast (orc4Y232C). To examine early replication dynamics on a genome-wide scale in orc4Y232C cells, we utilized an assay that was previously developed in our lab. This assay uses microarray hybridization to measure the levels of single stranded DNA exposed at replication forks. While we do not fully understand the molecular processes that give rise to peaks of different amplitudes—e.g., number of cells that have activated a particular origin vs. amount of ssDNA revealed at different forks—the results from different replicates of the experiment are highly reproducible. We find that origins that are known to fire early and are efficient produce the peaks of greatest magnitude, while later firing and less efficient origins produce smaller or no peaks in this assay. The characteristic time and/or efficiency of origin firing within the S phase is altered for at least 15% of the 300 yeast origins. Among the origins with delayed/reduced origin firing are normally early-firing origins adjacent to centromeres.

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Histone H3K36me3 regulates E2F transcription as part of the DNA replication stress checkpoint response

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2023-08-25 | GSE182775 | GEO

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Project description:In eukaryotes, the hetero-hexameric origin recognition complex (ORC) is responsible for assembling Mcm2-7 complex into a head-to-head double hexamer (DH), forming pre-replicative complex (pre-RC) that licenses origin DNA for replication initiation. This process is tightly controlled throughout the cell cycle to ensure accurate duplication of the genome. Here we show that the N-terminal intrinsically disordered region (IDR) of the yeast Orc2 subunit plays a critical role in promoting pre-RC assembly. We found that removing a short segment (residues 175-200) from Orc2-IDR or mutating a key isoleucine (194) in this region significantly inhibits replication initiation across the genome and causes cell death. Although the Orc2-IDR mutants can still assemble the ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) intermediate on DNA, the assembled mutant OCCM exhibits impaired ATP hydrolysis, preventing its conversion into Mcm2-7-ORC (MO) complex and subsequent DH formation. Interestingly, our in vitro assays showed that adding the Orc2-IDR peptide in the pre-RC reactions can rescue this defect. Furthermore, phosphorylation of this Orc2-IDR motif by S-cyclin dependent kinase (S-CDK) blocks its binding to Mcm2, leading to defective pre-RC assembly. Our findings provide crucial mechanistic insights into the multifaceted roles of ORC in modulating MCM loading to support origin licensing during the G1 phase and its regulation to restrict origin firing within the S phase.

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2022-02-28 | PXD031033 | Pride

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Project description:rs04-06_cdt1 - cdt1 - CDT1 is a protein of the pre-replication complex, and accumulates during the G1-S transition, thus play a major role in S-phase entry - Comparison of 3 independant RNAi lines Keywords: normal vs rnai mutant comparaison

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