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UHRF1 (Ubiquitin-like, containing PHD and RING Finger domains, 1) is a multi-domain protein that plays a critical role in recruiting DNMT1 (DNA methyltransferase 1) for replication-dependent DNA methylation maintenance. Emerging evidence has revealed that the protein stability and chromatin functions of UHRF1 are regulated in a cell cycle-dependent manner. To gain further insight into the functional regulation of UHRF1, we characterized the structure of the complex between UHRF1 and the deubiquitinase USP7. The first two UBL domains of USP7 bind to the polybasic region (PBR) of UHRF1, and this interaction is required for the USP7-mediated deubiquitination of UHRF1. Importantly, we find that the USP7-binding site of UHRF1 PBR overlaps with the region engaging an intramolecular interaction with the N-terminal tandem Tudor domain (TTD). We show that the USP7-UHRF1 interaction perturbs the TTD-PBR interaction of UHRF1, thereby shifting the conformation of UHRF1 from a TTD-“occluded” state to a state open for multivalent histone binding. Consistently, introduction of an USP7-interaction defective mutation to UHRF1 significantly reduces its chromatin association. Together, these results link USP7 interaction to the dynamic deubiquitination and chromatin association of UHRF1, and provides insights into the dynamic regulation of maintenance DNA methylation.ReferenceZhang ZM, Rothbart SB, Allison DF, Cai Q, Harrison JS, Li L, Wang Y, Strahl BD, Wang GG, Song J. An allosteric interaction links USP7 to deubiquitination and chromatin targeting of UHRF1. Cell Rep. (2015) 12(9):1400-6.