Impact of the Nucleosome Histone Core on the Structure and Dynamics of DNA-Containing Pyrimidine–Pyrimidone (6–4) Photoproduct
Résumé
The pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion, which constitutes a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with compaction proteins, and notably histones, affects the mechanism of its mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA containing 64-PP lesions within the nucleosome core particle by atomic-resolution molecular dynamics simulations at the multi-microsecond time scale. We demonstrate that the histone core exerts important mechanical restraints that largely decrease global DNA structural fluctuations. However, we also show that local DNA flexibility at the damaged site is enhanced, due to imperfect structural adaptation to restraints imposed by the histone core. In particular, if 64-PP faces the histone core and is therefore not directly accessible by the repair protein, the complementary strand facing the solvent exhibits higher flexibility than the corresponding strand in a naked, undamaged DNA. This may serve as an initial recognition signal for repair. Our simulations also pinpoint the structural role of proximal residues from the truncated histone tails.
Domaines
Chimie
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