The reference OMIM entry for this protein is 612167

Wd repeat-containing protein 48; wdr48
P80
Kiaa1449
Usp1-associated factor 1; uaf1

DESCRIPTION

WDR48, or UAF1, is the regulatory component of the nuclear USP1 (603478)-WDR48 deubiquitinating complex. By removing an activating ubiquitin modification, the USP1-WDR48 complex deactivates monoubiquitinated FANCD2 (613984) and monoubiquitinated PCNA (176740), which are required in DNA damage repair and translesional synthesis, respectively (Cohn et al., 2007).

CLONING

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned WDR48, which they called KIAA1449. The predicted 607-amino acid protein shares 43% identity with a 77-kD worm protein containing trp-asp (WD) repeats. RT-PCR ELISA detected high expression in testis and ovary and moderate expression in all other adult and fetal tissues examined. Within brain, expression was high in corpus callosum, caudate nucleus, and subthalamic nucleus and moderate in all other regions examined. By screening for T-lymphocyte proteins that could bind to the herpesvirus saimiri Tip protein, followed by immunoblot analysis, mass spectrometry, and PCR of a Jurkat T-cell cDNA library, Park et al. (2002) cloned full-length WDR48, which they called p80. The deduced 677-amino acid protein has a calculated molecular mass of 76.2 kD. It contains 8 potential N-terminal WD repeats and a C-terminal coiled-coil structure. Northern blot analysis detected a major 4.2-kb transcript and a minor 3.0-kb transcript in all tissues examined. Expression of the major transcript was somewhat higher in skeletal muscle, kidney, and placenta compared with other tissues. WDR48 had an apparent molecular mass of 80 kD by SDS-PAGE. Immunofluorescence analysis localized to WDR48 to late endosomes and lysosomes of Jurkat T cells.

GENE FUNCTION

Using protein pull-down assays and immunoprecipitation analysis, Park et al. (2002) showed that the N terminus of WDR48 interacted with the N-terminal ser-rich portion of Tip, while the WDR48 C terminus mediated lysosomal localization. Interaction of Tip with WDR48 induced lysosomal vesicle formation and, via the C-terminal region of Tip, recruitment of LCK (153390) to these lysosomal vesicles for degradation. Tip interactions with WDR48 and LCK resulted in downregulation of T-cell receptor (see 186830) and CD4 (186940) surface expression, respectively, leading to inhibition of T-lymphocyte signal transduction. By mass spectrometric analysis, Cohn et al. (2007) found that USP1 and UAF1 formed a stoichiometric complex that immunopurified from HeLa cell nuclear extracts. USP1 was present in the complex as both a full-length protein and as autocleaved N- and C-terminal fragments, with the catalytic cysteine box in the N-terminal fragment and the catalytic histidine box in the C-terminal fragment. UAF1 apparently bridged the 2 fragments together. USP1 alone showed little catalytic activity against monoubiquitinated FANCD2 or a synthetic monoubiquitinated fluorogenic substrate. However, addition of UAF1 increased the catalytic activity of USP1 up to 35-fold. Knockdown of UAF1 in HeLa cells via short hairpin RNA reduced the level of both full-length and hydrolyzed USP1, resulting in accumulation of monoubiquitinated FANCD2 and monoubiquitinated PCNA. Transcription of USP1 was rapidly suppressed and USP1 protein was degraded in response to ultraviolet irradiation, allowing cellular accumulation of monoubiquitinated FANCD2 for an effective DNA damage response. Cohn et al. (2007) noted that while all USP1 ... More on the omim web site

Subscribe to this protein entry history

Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

July 1, 2020: Protein entry updated
Automatic update: OMIM entry 612167 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).