Replication fork regression in vitro by the Werner syndrome protein (WRN): holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity.
Replication fork regression in vitro by the Werner syndrome protein (WRN): holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity.
复制标题
DOI：
10.1093/nar/gkm561
复制
发表时间：
2007
影响因子：
14.9
通讯作者：
Orren DK
中科院分区：
文献类型：
--
作者：
Machwe A;Xiao L;Lloyd RG;Bolt E;Orren DK
过早衰老和癌症易感性疾病Werner综合征源于WRN蛋白功能的丧失。WRN缺陷导致原代成纤维细胞的复制异常、对某些遗传毒性剂的敏感性、基因组不稳定性和早期复制衰老。作为RecQ解旋酶家族成员，WRN是DNA依赖性ATP酶和解旋酶，但也具有链退火和核酸外切酶活性。RecQ解旋酶被假定参与响应于复制阻断的途径，该途径可能由分叉回归启动。在这项研究中，一系列的模型复制叉基板被用来检查叉回归的WRN的能力。我们的研究结果表明，WRN催化叉回归和霍利迪结的形成。该过程是ATP依赖性反应，其对在叉连接处的前导臂上含有至少11-13 nt的单链缺口的叉特别有效。重要的是，WRN核酸外切酶活性通过消化前导子链，增强了前导臂上具有较小缺口的叉的退化，从而产生了退化的最佳结构。我们的研究结果表明，多个活动的WRN合作，以促进复制叉回归。这些发现，沿着WRN缺陷的既定细胞后果，强烈支持WRN在阻断的复制叉消退中的作用。
The premature aging and cancer-prone disease Werner syndrome stems from loss of WRN protein function. WRN deficiency causes replication abnormalities, sensitivity to certain genotoxic agents, genomic instability and early replicative senescence in primary fibroblasts. As a RecQ helicase family member, WRN is a DNA-dependent ATPase and unwinding enzyme, but also possesses strand annealing and exonuclease activities. RecQ helicases are postulated to participate in pathways responding to replication blockage, pathways possibly initiated by fork regression. In this study, a series of model replication fork substrates were used to examine the fork regression capability of WRN. Our results demonstrate that WRN catalyzes fork regression and Holliday junction formation. This process is an ATP-dependent reaction that is particularly efficient on forks containing single-stranded gaps of at least 11–13 nt on the leading arm at the fork junction. Importantly, WRN exonuclease activity, by digesting the leading daughter strand, enhances regression of forks with smaller gaps on the leading arm, thus creating an optimal structure for regression. Our results suggest that the multiple activities of WRN cooperate to promote replication fork regression. These findings, along with the established cellular consequences of WRN deficiency, strongly support a role for WRN in regression of blocked replication forks.
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人RECQ5BETA解旋酶在合成DNA结构上促进链交换，类似于停滞的复制叉。
影响因子：
14.9
作者：
Kanagaraj, Radhakrishnan;Saydam, Nurten;Garcia, Patrick L.;Zheng, Lu;Janscak, Pavel
通讯作者：
Janscak, Pavel
影响因子：
7.7
作者：
Flores, MJ;Bidnenko, V;Michel, B
通讯作者：
Michel, B
DOI：
10.1073/pnas.0600785103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Courcelle, Charmain T.;Chow, Kin-Hoe;Courcelle, Justin
通讯作者：
Courcelle, Justin
影响因子：
5.3
作者：
Karmakar, P;Bohr, VA
通讯作者：
Bohr, VA
影响因子：
5.3
作者：
Goto, M
通讯作者：
Goto, M