DNA damage detection in nucleosomes involves DNA register shifting

Article

关键词: PIGMENTOSUM GROUP-E;    BEAM-INDUCED MOTION;    UBIQUITIN LIGASE;    XERODERMA-PIGMENTOSUM;    STRUCTURAL BASIS;    HISTONE H2A;    PARTICLE;    REPAIR;    RECOGNITION;    RESOLUTION;   

DOI  :  10.1038/s41586-019-1259-3

来源: SCIE

【 摘 要 】

Access to DNA packaged in nucleosomes is critical for gene regulation, DNA replication and DNA repair. In humans, the UV-damaged DNA-binding protein (UV-DDB) complex detects UV-light-induced pyrimidine dimers throughout the genome; however, it remains unknown how these lesions are recognized in chromatin, in which nucleosomes restrict access to DNA. Here we report cryo-electron microscopy structures of UV-DDB bound to nucleosomes bearing a 6-4 pyrimidine-pyrimidone dimer or a DNA-damage mimic in various positions. We find that UV-DDB binds UV-damaged nucleosomes at lesions located in the solvent-facing minor groove without affecting the overall nucleosome architecture. In the case of buried lesions that face the histone core, UV-DDB changes the predominant translational register of the nucleosome and selectively binds the lesion in an accessible, exposed position. Our findings explain how UV-DDB detects occluded lesions in strongly positioned nucleosomes, and identify slide-assisted site exposure as a mechanism by which high-affinity DNA-binding proteins can access otherwise occluded sites in nucleosomal DNA.

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