当前位置: X-MOL 学术Nucleic Acids Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Mechanism of lesion verification by the human XPD helicase in nucleotide excision repair
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2022-06-17 , DOI: 10.1093/nar/gkac496
Iwen Fu 1 , Hong Mu 1 , Nicholas E Geacintov 2 , Suse Broyde 1
Affiliation  

In nucleotide excision repair (NER), the xeroderma pigmentosum D helicase (XPD) scans DNA searching for bulky lesions, stalls when encountering such damage to verify its presence, and allows repair to proceed. Structural studies have shown XPD bound to its single-stranded DNA substrate, but molecular and dynamic characterization of how XPD translocates on undamaged DNA and how it stalls to verify lesions remains poorly understood. Here, we have performed extensive all-atom MD simulations of human XPD bound to undamaged and damaged ssDNA, containing a mutagenic pyrimidine (6−4) pyrimidone UV photoproduct (6−4PP), near the XPD pore entrance. We characterize how XPD responds to the presence of the DNA lesion, delineating the atomistic-scale mechanism that it utilizes to discriminate between damaged and undamaged nucleotides. We identify key amino acid residues, including FeS residues R112, R196, H135, K128, Arch residues E377 and R380, and ATPase lobe 1 residues 215−221, that are involved in damage verification and show how movements of Arch and ATPase lobe 1 domains relative to the FeS domain modulate these interactions. These structural and dynamic molecular depictions of XPD helicase activity with unmodified DNA and its inhibition by the lesion elucidate how the lesion is verified by inducing XPD stalling.

中文翻译:

人 XPD 解旋酶在核苷酸切除修复中的损伤验证机制

在核苷酸切除修复 (NER) 中,色素性干皮病 D 解旋酶 (XPD) 扫描 DNA 以寻找大块病变,在遇到此类损伤时停止以验证其存在,并允许进行修复。结构研究表明 XPD 与其单链 DNA 底物结合,但对 XPD 如何在未受损 DNA 上易位以及它如何停止以验证病变的分子和动力学表征仍然知之甚少。在这里,我们对与未损坏和损坏的 ssDNA 结合的人类 XPD 进行了广泛的全原子 MD 模拟,在 XPD 孔入口附近包含诱变嘧啶 (6−4) 嘧啶酮 UV 光产物 (6−4PP)。我们描述了 XPD 如何响应 DNA 损伤的存在,描述了它用来区分受损和未受损核苷酸的原子尺度机制。我们确定了参与损伤验证的关键氨基酸残基,包括 FeS 残基 R112、R196、H135、K128、Arch 残基 E377 和 R380,以及 ATPase 叶 1 残基 215-221,并显示 Arch 和 ATPase 叶 1 域的运动相对于 FeS 域调节这些相互作用。这些具有未修饰 DNA 的 XPD 解旋酶活性的结构和动态分子描述及其对病变的抑制阐明了如何通过诱导 XPD 停滞来验证病变。
更新日期:2022-06-17
down
wechat
bug