DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor
JOURNAL OF MOLECULAR CELL BIOLOGY
Authors: Schabla, N. Max; Mondal, Koushik; Swanson, Patrick C.
Abstract
Cullin-RING ligases (CRLs) comprise a large group of modular eukaryotic E3 ubiquitin ligases. Within this family, the CRL4 ligase (consisting of the Cullin4 [CUL4] scaffold protein, the Rbx1 RING finger domain protein, the DNA damage-binding protein 1 [DDB1], and one of many DDB1-associated substrate receptor proteins) has been intensively studied in recent years due to its involvement in regulating various cellular processes, its role in cancer development and progression, and its subversion by viral accessory proteins. Initially discovered as a target for hijacking by the human immunodeficiency virus accessory protein r, the normal targets and function of the CRL4 substrate receptor protein DDB1-Cul4-associated factor 1 (DCAF1; also known as VprBP) had remained elusive, but newer studies have begun to shed light on these questions. Here, we review recent progress in understanding the diverse physiological roles of this DCAF1 in supporting various general and cell type-specific cellular processes in its context with the CRL4 E3 ligase, as well as another HECT-type E3 ligase with which DCAF1 also associates, called EDD/UBR5. We also discuss emerging questions and areas of future study to uncover the dynamic roles of DCAF1 in normal physiology.
CDK Inhibitor p21 Is Degraded by a Proliferating Cell Nuclear Antigen-coupled Cul4-DDB1(Cdt2) Pathway during S Phase and after UV Irradiation
JOURNAL OF BIOLOGICAL CHEMISTRY
Authors: Nishitani, Hideo; Shiomi, Yasushi; Iida, Hiroka; Michishita, Masato; Takami, Toshihiro; Tsurimoto, Toshiki
Abstract
Previous reports showed that chromatin-associated PCNA couples DNA replication with Cul4-DDB1(Cdt2)-dependent proteolysis of the licensing factor Cdt1. The CDK inhibitor p21, another PCNA-binding protein, is also degraded both in S phase and after UV irradiation. Here we show that p21 is degraded by the same ubiquitin-proteasome pathway as Cdt1 in HeLa cells. When PCNA or components of Cul4-DDB1(Cdt2) were silenced or when the PCNA binding site on p21 was mutated, degradation of p21 was prevented both in S phase and after UV irradiation. p21 was co-immunoprecipitated with Cul4A and DDB1 proteins when expressed in cells. The purified Cul4A-DDB1(Cdt2) complex ubiquitinated p21 in vitro. Consistently, p21 protein levels are low during S phase and increase around G(2) phase. Mutational analysis suggested that in addition to the PCNA binding domain, its flanking regions are also important for recognition by Cul4-DDB1(Cdt2). Our findings provide a new aspect of proteolytic control of p21 during the cell cycle.
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