Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Ultraviolet (UV) radiation causes DNA damage, primarily through pyrimidine photodimers.
• Nucleotide excision repair (NER) pathway repairs these photolesions.
• The DDB1-DDB2 complex is crucial for initial UV lesion detection in vivo.
• Photolesions possess biophysical properties similar to undamaged DNA, challenging surveillance proteins.

Purpose of the Study:

• To elucidate the structural basis of UV lesion recognition by the DDB1-DDB2 complex.
• To understand the mechanism by which DDB2 detects photolesions.
• To provide insights into DNA damage recognition in chromatin.

Main Methods:

• X-ray crystallography was used to determine the structures of the DDB1-DDB2 complex.
• Structures were obtained for the complex alone, bound to DNA with a 6-4 pyrimidine-pyrimidone photodimer (6-4PP) lesion, and bound to DNA with an abasic site.

Main Results:

• The WD40 domain of DDB2 exclusively binds the UV lesion.
• A DDB2 hairpin inserts into the DNA minor groove, extruding the photodimer into a binding pocket.
• The DNA duplex is kinked by approximately 40 degrees at the lesion site.
• DDB2 exhibits localized probing and proofreading within its binding pocket, enabling detection of refractory lesions.

Conclusions:

• The DDB1-DDB2 complex employs a unique structural mechanism for precise UV photolesion detection.
• This mechanism allows DDB2 to identify lesions that evade other damage surveillance proteins.
• The findings offer insights into DNA damage recognition within chromatin.
• A potential mechanism for CUL4 ubiquitin ligase recruitment to damage sites is suggested.