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首页> 外文期刊>Biochemistry >DNA translocation by human uracil DNA glycosylase: The case of single-stranded DNA and clustered uracils
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DNA translocation by human uracil DNA glycosylase: The case of single-stranded DNA and clustered uracils

机译：人尿嘧啶DNA糖基化酶的DNA易位：单链DNA和簇状尿嘧啶的情况

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Human uracil DNA glycosylase (hUNG) plays a central role in DNA repair and programmed mutagenesis of Ig genes, requiring it to act on sparsely or densely spaced uracil bases located in a variety of contexts, including U/A and U/G base pairs, and potentially uracils within single-stranded DNA (ssDNA). An interesting question is whether the facilitated search mode of hUNG, which includes both DNA sliding and hopping, changes in these different contexts. Here we find that hUNG uses an enhanced local search mode when it acts on uracils in ssDNA, and also, in a context where uracils are densely clustered in duplex DNA. In the context of ssDNA, hUNG performs an enhanced local search by sliding with a mean sliding length larger than that of double-stranded DNA (dsDNA). In the context of duplex DNA, insertion of high-affinity abasic product sites between two uracil lesions serves to significantly extend the apparent sliding length on dsDNA from 4 to 20 bp and, in some cases, leads to directionally biased 3′ → 5′ sliding. The presence of intervening abasic product sites mimics the situation where hUNG acts iteratively on densely spaced uracils. The findings suggest that intervening product sites serve to increase the amount of time the enzyme remains associated with DNA as compared to nonspecific DNA, which in turn increases the likelihood of sliding as opposed to falling off the DNA. These findings illustrate how the search mechanism of hUNG is not predetermined but, instead, depends on the context in which the uracils are located.
机译：人尿嘧啶DNA糖基化酶（hUNG）在DNA修复和Ig基因的程序诱变中起着核心作用，要求它对稀疏或密集的尿嘧啶碱基起作用，尿嘧啶碱基位于各种环境中，包括U / A和U / G碱基对，以及单链DNA（ssDNA）中的尿嘧啶。一个有趣的问题是，hUNG的便利搜索模式（包括DNA滑动和跳跃）是否在这些不同情况下发生了变化。在这里，我们发现hUNG作用于ssDNA中的尿嘧啶时，以及在尿嘧啶密集地聚集在双链体DNA中的情况下，使用增强的局部搜索模式。在ssDNA的情况下，hUNG通过滑动的平均滑动长度大于双链DNA（dsDNA）的滑动长度来执行增强的局部搜索。在双链DNA的情况下，在两个尿嘧啶病变之间插入高亲和力无碱基产物位点可显着延长dsDNA上的表观滑动长度从4到20 bp，在某些情况下会导致方向性偏向3'→5'滑动。中间无碱基产物位点的存在模仿了hUNG反复作用于密集尿嘧啶的情况。研究结果表明，与非特异性DNA相比，中间产物位点可增加酶与DNA结合的时间，从而增加了从DNA脱落的可能性。这些发现说明了hUNG的搜索机制是如何预先确定的，而是取决于尿嘧啶所在的环境。

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