The HelQ human DNA repair helicase utilizes a PWI-like domain for DNA loading through interaction with RPA, triggering DNA unwinding by the HelQ helicase core.
The HelQ human DNA repair helicase utilizes a PWI-like domain for DNA loading through interaction with RPA, triggering DNA unwinding by the HelQ helicase core.
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HelQ人DNA修复解旋酶利用PWI样结构域通过与RPA相互作用进行DNA加载，通过HelQ解旋酶核心触发DNA解旋。
DOI：
10.1093/narcan/zcaa043
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发表时间：
2021-03
期刊：
影响因子：
5.1
通讯作者：
Bolt EL
中科院分区：
文献类型：
--
作者：
Jenkins T;Northall SJ;Ptchelkine D;Lever R;Cubbon A;Betts H;Taresco V;Cooper CDO;McHugh PJ;Soultanas P;Bolt EL
基因组不稳定是致癌的一个特征性使能因素。HelQ解旋酶是人类DNA维持系统的一个组成部分，它可以防止或逆转DNA复制过程中产生的基因组不稳定。在这里，我们提供了支撑HelQ功能的分子机制的细节——它通过与复制蛋白A （RPA）的相互作用被募集到ssDNA上，随后HelQ沿着ssDNA易位。通过鉴定和表征其pwi样结构域，我们首次描述了HelQ的非催化n端区域的功能作用。我们提供的证据表明，HelQ的这个结构域介导与RPA的相互作用，RPA协调将螺旋酶结构域加载到ssDNA上。一旦HelQ被装载到ssDNA上，催化位点上的ATP-Mg2+结合激活了解旋酶核心，并触发了ssDNA作为二聚体的易位。此外，我们确定了HelQ-ssDNA相互作用对易位机制至关重要。我们的数据是对HelQ功能机制的新颖和详细的见解，这与理解人类细胞如何避免基因组不稳定引发癌症，以及细胞如何对依赖DNA交联剂的治疗产生耐药性有关。
Genome instability is a characteristic enabling factor for carcinogenesis. HelQ helicase is a component of human DNA maintenance systems that prevent or reverse genome instability arising during DNA replication. Here, we provide details of the molecular mechanisms that underpin HelQ function—its recruitment onto ssDNA through interaction with replication protein A (RPA), and subsequent translocation of HelQ along ssDNA. We describe for the first time a functional role for the non-catalytic N-terminal region of HelQ, by identifying and characterizing its PWI-like domain. We present evidence that this domain of HelQ mediates interaction with RPA that orchestrates loading of the helicase domains onto ssDNA. Once HelQ is loaded onto the ssDNA, ATP-Mg2+ binding in the catalytic site activates the helicase core and triggers translocation along ssDNA as a dimer. Furthermore, we identify HelQ-ssDNA interactions that are critical for the translocation mechanism. Our data are novel and detailed insights into the mechanisms of HelQ function relevant for understanding how human cells avoid genome instability provoking cancers, and also how cells can gain resistance to treatments that rely on DNA crosslinking agents.