Helq acts in parallel to Fancc to suppress replication-associated genome instability.
Helq acts in parallel to Fancc to suppress replication-associated genome instability.
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DOI：
10.1093/nar/gkt676
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发表时间：
2013-12
影响因子：
14.9
通讯作者：
Shima N
中科院分区：
文献类型：
--
作者：
Luebben SW;Kawabata T;Akre MK;Lee WL;Johnson CS;O'Sullivan MG;Shima N
HELQ是在古细菌和后生动物中发现的超家族2 DNA解旋酶。它涉及处理停滞的复制叉和修复DNA双链断裂和链间交联。虽然先前的研究表明HELQ可能参与Fanconi贫血（FA）途径，这是脊椎动物链间交联修复的主要机制，但这种联系仍然难以捉摸。在这里，我们使用Helqgt和Fancc -菌株在小鼠中研究了这个问题。与缺乏Fancc （FA核心复合物的一种成分）的Fancc - / -小鼠相比，Helqgt/gt小鼠表现出轻度的FA样表型，包括性腺功能减退和细胞对交联剂丝裂霉素c的敏感性。然而，与Fancc - / -原代成纤维细胞不同，Helqgt/gt细胞具有完整的FANCD2单泛素化和病灶形成。值得注意的是，在所有被检测的性状中，Helq与Fancc是非上位性的，如Helqgt/gt；Fancc−/−双突变体的表型明显比单突变体差。重要的是，这对自发染色体不稳定性的抑制最为明显，如微核和53BP1核体，这是持续停滞的复制分叉的已知后果。这些发现表明，哺乳动物HELQ通过一种不同于FANCC功能的机制，有助于在无挑战条件下的基因组稳定性。
HELQ is a superfamily 2 DNA helicase found in archaea and metazoans. It has been implicated in processing stalled replication forks and in repairing DNA double-strand breaks and inter-strand crosslinks. Though previous studies have suggested the possibility that HELQ is involved in the Fanconi anemia (FA) pathway, a dominant mechanism for inter-strand crosslink repair in vertebrates, this connection remains elusive. Here, we investigated this question in mice using the Helqgt and Fancc− strains. Compared with Fancc−/− mice lacking FANCC, a component of the FA core complex, Helqgt/gt mice exhibited a mild of form of FA-like phenotypes including hypogonadism and cellular sensitivity to the crosslinker mitomycin C. However, unlike Fancc−/− primary fibroblasts, Helqgt/gt cells had intact FANCD2 mono-ubiquitination and focus formation. Notably, for all traits examined, Helq was non-epistatic with Fancc, as Helqgt/gt;Fancc−/− double mutants displayed significantly worsened phenotypes than either single mutant. Importantly, this was most noticeable for the suppression of spontaneous chromosome instability such as micronuclei and 53BP1 nuclear bodies, known consequences of persistently stalled replication forks. These findings suggest that mammalian HELQ contributes to genome stability in unchallenged conditions through a mechanism distinct from the function of FANCC.
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影响因子：
4.5
作者：
Holloway JK;Mohan S;Balmus G;Sun X;Modzelewski A;Borst PL;Freire R;Weiss RS;Cohen PE
通讯作者：
Cohen PE
DOI：
10.1073/pnas.1232231100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Hendricks, CA;Almeida, KH;Engelward, BP
通讯作者：
Engelward, BP
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影响因子：
5.3
作者：
Gao, Yong;He, Yisha;Shen, Hongbing
通讯作者：
Shen, Hongbing
影响因子：
4.8
作者：
Fujikane, R;Komori, K;Ishino, Y
通讯作者：
Ishino, Y
影响因子：
21.3
作者：
Chan, Kok Lung;Palmai-Pallag, Timea;Hickson, Ian D.
通讯作者：
Hickson, Ian D.