Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein

In mammalian nucleotide excision repair, the DDB1–
DDB2 complex recognizes UV-induced DNA photolesions
and facilitates recruitment of the XPC complex.
Upon binding to damaged DNA, the Cullin 4
ubiquitin ligase associated with DDB1–DDB2 is activated
and ubiquitinates DDB2 and XPC. The structurally
disordered N-terminal tail of DDB2 contains
seven lysines identified as major sites for ubiquitination
that target the protein for proteasomal degradation;
however, the precise biological functions of
these modifications remained unknown. By exogenous
expression of mutant DDB2 proteins in normal
human fibroblasts, here we show that the N-terminal
tail of DDB2 is involved in regulation of cellular responses
to UV. By striking contrast with behaviors
of exogenous DDB2, the endogenous DDB2 protein
was stabilized even after UV irradiation as a function
of the XPC expression level. Furthermore, XPC competitively
suppressed ubiquitination of DDB2in vitro,
and this effect was significantly promoted by centrin-
2, which augments the DNA damage-recognition activity
of XPC. Based on these findings, we propose
that in cells exposed to UV, DDB2 is protected by XPC
from ubiquitination and degradation in a stochastic
manner; thus XPC allows DDB2 to initiate multiple
rounds of repair events, thereby contributing to the
persistence of cellular DNA repair capacity.

書誌情報

Nucleic Acids Research

巻 43, 号 3, p. 1700-1713, 発行日 2015-01

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Oxford Journals

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DOI

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2023-05-15 23:44:09.198257

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