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USP7 and VCPFAF1 define the SUMO/Ubiquitin landscape at DNA replication forks

ABSTRACT: The AAA+ ATPase VCP regulates the extraction of SUMO and/or ubiquitin modified factors from chromatin. We previously showed that active DNA synthesis is associated with a SUMO-high and ubiquitin-low environment that is maintained by the deubiquitylase USP7. Here we unveil a functional cooperation between USP7 and VCP in the control of DNA replication conserved from Caenorhabditis elegans to mammals. The function of VCP during DNA replication is mediated by its cofactor FAF1, which facilitates the extraction of SUMOylated proteins that accumulate on chromatin upon USP7 inhibition. Supporting this cooperative role, the inactivation of the orthologues of USP7 and FAF1 is synthetic lethal in C. elegans, and USP7 and FAF1 inhibitors display synergistic toxicity. Together, these results reveal a coordinated activity of USP7 and VCPFAF1 in limiting SUMOylation at active replication forks and promoting the extraction and degradation of ubiquitylated proteins.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Eduardo Zarzuela

LAB HEAD: Javier Muñoz

PROVIDER: PXD018623 | Pride | 2021-09-12

REPOSITORIES: Pride

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			Action	DRS
	20161215_EZ_VCP_Bait_DMSO_01.raw	Raw
	20161215_EZ_VCP_Bait_DMSO_02.raw	Raw
	20161215_EZ_VCP_Bait_NMS_01.raw	Raw
	20161215_EZ_VCP_Bait_NMS_02.raw	Raw
	20161215_EZ_VCP_Bait_p22_01.raw	Raw

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Project description:Post-translational modification of proteins by ubiquitin (UQ) and UQ-like modifiers is emerging as a central pathway in DNA replication. We previously showed that chromatin in the vicinity of replisomes is rich in SUMO and depleted in UQ, whereas an opposite pattern is observed in mature chromatin. How this SUMO-rich/UQ-low environment is maintained at replisomes is not known. Here we identify USP7 as a SUMO deubiquitinase that localizes to replication forks and is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 prevents their ubiquitination. Chemical inhibition or genetic deletion of USP7 leads to the accumulation of UQ on SUMOylated proteins, which are displaced from the replisomes. Our findings provide a model to explain the differential accumulation of SUMO and UQ in replication forks versus mature chromatin, and identify an essential role of USP7 that should be taken into account for the use of USP7 inhibitors as anticancer agents.

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Project description:USP7, a ubiquitin-specific peptidase (USP), plays an important role in many cellular processes through its catalytic deubiquitination of various substrates. However, its nuclear function to shape the transcriptional network in mouse embryonic stem cells (mESCs) remains poorly understood. Here, we report that USP7 maintains mESCs identity through both catalytic activity-dependent and -independent repression of lineage differentiation genes. Usp7 depletion attenuates SOX2 level and derepresses lineage differentiation genes thereby compromising mESCs pluripotency. Mechanistically, USP7 deubiquitinates and stabilizes SOX2 to repress mesoendodermal (ME) lineage genes. Moreover, USP7 assembles into RYBP-variant Polycomb repressive complex 1 and contributes to Polycomb chromatin-mediated repression of ME lineage genes in a catalytic activity-dependent manner. Importantly, USP7 deficient in its deubiquitination function is able to maintain RYBP binding to chromatin for repressing primitive endoderm-associated genes. Overall, our study demonstrates that USP7 harbors both catalytic and non-catalytic activity to repress different lineage differentiation genes thereby revealing a previously unrecognized role in controlling gene expression for maintaining mESCs identity.

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Integrative Network Analysis Reveals USP7 Haploinsufficiency Inhibits E-protein Activity in Pediatric T-lineage Acute Lymphoblastic Leukemia (T-ALL)

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