Abstract
Global-genome nucleotide excision repair (GG-NER) prevents genome instability by excising a wide range of different DNA base adducts and crosslinks induced by chemical carcinogens, ultraviolet (UV) light or intracellular side products of metabolism. As a versatile damage sensor, xeroderma pigmentosum group C (XPC) protein initiates this generic defense reaction by locating the damage and recruiting the subunits of a large lesion demarcation complex that, in turn, triggers the excision of aberrant DNA by endonucleases. In the very special case of a DNA repair response to UV radiation, the function of this XPC initiator is tightly controlled by the dual action of cullin-type CRL4DDB2 and sumo-targeted RNF111 ubiquitin ligases. This twofold protein ubiquitination system promotes GG-NER reactions by spatially and temporally regulating the interaction of XPC protein with damaged DNA across the nucleosome landscape of chromatin. In the absence of either CRL4DDB2 or RNF111, the DNA excision repair of UV lesions is inefficient, indicating that these two ubiquitin ligases play a critical role in mitigating the adverse biological effects of UV light in the exposed skin.
Highlights
All organisms are constantly under attack by environmental and endogenous DNA-damaging agents that endanger the sequence fidelity of their genomes
The genome instability observed in UV-irradiated cells after p97 depletion was reversed by concurrent down-regulation of DDB2 or xeroderma pigmentosum group C (XPC) (Puumalainen et al, 2014). These findings suggested that the uncontrolled accumulation of DDB2 or XPC is detrimental and that a tight regulation of their levels in chromatin is essential for genome stability
The XPC complex provides the generic initiator of Global-genome nucleotide excision repair (GG-nucleotide excision repair (NER)) activity on the basis of its ability to sense the damagedependent disruption of base pairs in double-stranded DNA and recruit the XPD scanner for bulky lesion recognition
Summary
In the very special case of a DNA repair response to UV radiation, the function of this XPC initiator is tightly controlled by the dual action of cullin-type CRL4DDB2 and sumo-targeted RNF111 ubiquitin ligases. This twofold protein ubiquitination system promotes GG-NER reactions by spatially and temporally regulating the interaction of XPC protein with damaged DNA across the nucleosome landscape of chromatin. In the absence of either CRL4DDB2 or RNF111, the DNA excision repair of UV lesions is inefficient, indicating that these two ubiquitin ligases play a critical role in mitigating the adverse biological effects of UV light in the exposed skin
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