Title | UV-damaged DNA-binding proteins are targets of CUL-4A-mediated ubiquitination and degradation. |
Publication Type | Journal Article |
Year of Publication | 2001 |
Authors | Chen X, Zhang Y, Douglas L, Zhou P |
Journal | J Biol Chem |
Volume | 276 |
Issue | 51 |
Pagination | 48175-82 |
Date Published | 2001 Dec 21 |
ISSN | 0021-9258 |
Keywords | Animals, Cell Line, Cricetinae, Cullin Proteins, Cytoplasm, DNA-Binding Proteins, Humans, Hydrolysis, Neoplasm Proteins, Ubiquitin, Ultraviolet Rays |
Abstract | Cul-4A, which encodes a member of the cullin family subunit of ubiquitin-protein ligases, is expressed at abnormally high levels in many tumor cells. CUL-4A can physically associate with the damaged DNA-binding protein (DDB), which is composed of two subunits, p125 and p48. DDB binds specifically to UV-damaged DNA and is believed to play a role in DNA repair. We report here that CUL-4A stimulates degradation of p48 through the ubiquitin-proteasome pathway, resulting in an overall decrease in UV-damaged DNA binding activity. The R273H mutant of p48 identified from a xeroderma pigmentosium (group E) patient is not subjected to CUL-4A-mediated proteolysis, consistent with its inability to bind CUL-4A. p125 is also an unstable protein, and its ubiquitination is stimulated by CUL-4A. However, the abundance of p125 is not dramatically altered by Cul-4A overexpression. UV irradiation inhibits p125 degradation, which is temporally coupled to the UV-induced translocation of p125 from the cytoplasm into the nucleus. CUL-4A is localized primarily in the cytoplasm. These findings identify DDB subunits as the first substrates of the CUL-4A ubiquitination machinery and suggest that abnormal expression of Cul-4A results in reduced p48 levels, thus impairing the ability of DDB in lesion recognition and DNA repair in tumor cells. |
DOI | 10.1074/jbc.M106808200 |
Alternate Journal | J Biol Chem |
PubMed ID | 11673459 |
Related Faculty:
Pengbo Zhou, Ph.D.