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The E3 Ubiquitin Ligase Nedd4L Acts as a Checkpoint Against Activation in Quiescent Muscle Stem Cells

ABSTRACT: The E3 Ubiquitin Ligase Nedd4L Acts as a Checkpoint Against Activation in Quiescent Muscle Stem Cells

PROVIDER: PRJNA962010 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24314713.fastq.gz	Fastqsanger.gz
	SRR24314714.fastq.gz	Fastqsanger.gz
	SRR24314715.fastq.gz	Fastqsanger.gz
	SRR24314716.fastq.gz	Fastqsanger.gz
	SRR24314717.fastq.gz	Fastqsanger.gz

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Project description:Plant Homeo Domain (PHD) is a versatile chromatin reader/effector module which recognizes methylated, acetylated or unmodified histone substrates and regulates cellular gene expression programs. Although PHD domains shows selective epigenetic recognition of methylated, acetylated and unmodified histone substrates, there has been no previous report on its catalytic function regulating malignant transformation of cells. Here we report that PHD finger of UBR7 (Ubiquitin Protein Ligase E3 Component N-Recognin 7 (Putative)), in isolation or in context of full length protein, harbors E3 ubiquitin ligase activity towards monoubiquitination of histone H2B at lysine 120 . Knockdown of UBR7 in MCF10a and breast cancer cells decreased H2BK120ub both at the global levels and on specific genes. Conversely, overexpression of wild type, but not catalytic mutant, rescued H2BK120ub levels. Low UBR7 expression was associated with basal-like and triple negative breast cancers as well as showed poor expression in metastatic tumors. Consistently, UBR7 loss resulted in invasion properties, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 reduced cell growth, invasion and tumor growth in mouse fat pad. Mechanistically, UBR7 reduced H2BK120ub gene body of cell-adhesion related genes as well as gene expression including on CDH4 gene. Importantly, rebuilding CDH4 levels rescued invasion phenotypes seen in UBR7-low cells. Collectively, our results establish that UBR7 PHD has novel H2B ubiquitin ligase activity and it suppresses tumor growth in basal-like breast cancers.

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