Mechanism of lesion verification by the human XPD helicase in nucleotide excision repair.
Mechanism of lesion verification by the human XPD helicase in nucleotide excision repair.
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DOI：
10.1093/nar/gkac496
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发表时间：
2022-07-08
影响因子：
14.9
通讯作者：
Broyde, Suse
中科院分区：
文献类型：
--
作者：
Fu, Iwen;Mu, Hong;Geacintov, Nicholas E.;Broyde, Suse
在核苷酸切除修复（NER）中，着色性干皮病D解旋酶（XPD）扫描DNA寻找大的损伤，当遇到这种损伤时停止以验证其存在，并允许修复继续进行。结构研究表明XPD与其单链DNA底物结合，但XPD如何在未受损DNA上易位以及如何阻止以验证病变的分子和动态表征仍然知之甚少。在这里，我们对结合到未受损和受损ssDNA的人XPD进行了广泛的全原子MD模拟，在XPD孔入口附近含有诱变嘧啶（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，描绘了它用来区分受损和未受损核苷酸的原子级机制。我们确定了关键氨基酸残基，包括FeS残基R112，R196，H135，K128，Arch残基E377和R380，以及ATP酶叶1残基215 - 221，这些残基参与损伤验证，并显示Arch和ATP酶叶1结构域相对于FeS结构域的运动如何调节这些相互作用。XPD解旋酶活性与未修饰DNA的这些结构和动态分子图及其被病变抑制阐明了如何通过诱导XPD停滞来验证病变。XPD-ssDNA复合物的MD模拟表明，XPD打开其孔以允许未受损的DNA移位，并缩小其孔以阻止病变。
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. MD simulations of XPD–ssDNA complexes show that XPD opens its pore to allow undamaged DNA to translocate and narrows its pore to stall the lesion.
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影响因子：
16
作者：
Coin, Frederic;Oksenych, Valentyn;Egly, Jean-Marc
通讯作者：
Egly, Jean-Marc
影响因子：
4.8
作者：
Buechner, Claudia N.;Heil, Korbinian;Tessmer, Ingrid
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Tessmer, Ingrid
影响因子：
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作者：
Dubaele, S;De Santis, LP;Egly, JM
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Egly, JM
DOI：
10.1073/pnas.1213981110
发表时间：
2013-02-19
影响因子：
11.1
作者：
Abdulrahman, Wassim;Iltis, Izarn;Poterszman, Arnaud
通讯作者：
Poterszman, Arnaud
影响因子：
5.6
作者：
D'Orazio J;Jarrett S;Amaro-Ortiz A;Scott T
通讯作者：
Scott T