HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis.
HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis.
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作者：
链间交联（ICL）的修复需要S期内检查点和Fanconi贫血（FA）通路的协调作用，促进ICL切割、跨损伤合成和同源重组（综述见）。以前的研究表明，3′-5′超家族2解旋酶HELQ/Hel 308参与了D. melanogaster（称为Mus 301或Spn-C）和C. elegans（称为Helq-1或Hel-308）。尽管体外分析表明HELQ优先解旋具有3′ ssDNA突出端的合成复制叉底物，并且在沿着DNA易位时也破坏蛋白质/DNA相互作用，但对其在哺乳动物生物中的功能知之甚少。在这里，我们报告说，HELQ解旋酶缺陷小鼠表现出生育力低下，生殖细胞磨损，ICL敏感性和肿瘤易感性，与HelQ杂合子小鼠表现出类似的，虽然不太严重，表型比空，表明单倍不足。我们建立了HELQ直接与RAD 51 paradigm复合物BCDX 2相互作用，并与FA途径平行发挥作用，以促进受损复制叉处的高效HR。因此，我们的研究结果揭示了HELQ在复制偶联DNA修复，生殖细胞的维护和肿瘤抑制在哺乳动物中的关键作用。
Repair of interstrand crosslinks (ICLs) requires the coordinate action of the intra-S phase checkpoint and the Fanconi Anemia (FA) pathway, which promote ICL incision, translesion synthesis, and homologous recombination (reviewed in ). Previous studies have implicated the 3′-5′ superfamily 2 helicase HELQ/Hel308 in ICL repair in D. melanogaster (known as Mus301 or Spn-C) and C. elegans (known as Helq-1 or Hel-308). While in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3′ ssDNA overhangs and also disrupts protein/DNA interactions while translocating along DNA, little is known regarding its functions in mammalian organisms. Here we report that HELQ helicase-deficient mice exhibit subfertility, germ cell attrition, ICL sensitivity and tumour predisposition, with HelQ heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. We establish that HELQ interacts directly with the RAD51 paralog complex, BCDX2, and functions in parallel to the FA pathway to promote efficient HR at damaged replication forks. Thus, our results reveal a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour suppression in mammals.
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影响因子：
5.2
作者：
Parmar, Kalindi;Kim, Jungmin;Sykes, Stephen M.;Shimamura, Akiko;Stuckert, Patricia;Zhu, Kaya;Hamilton, Abigail;Deloach, Mary Kathryn;Kutok, Jeffery L.;Akashi, Koichi;Gilliland, D. Gary;D'andrea, Alan
通讯作者：
D'andrea, Alan
影响因子：
64.5
作者：
Kratz, Katja;Schoepf, Barbara;Jiricny, Josef
通讯作者：
Jiricny, Josef
DOI：
10.1073/pnas.111005698
发表时间：
2001-07-17
影响因子：
11.1
作者：
Masson, JY;Stasiak, AZ;West, SC
通讯作者：
West, SC
DOI：
10.1073/pnas.0804424105
发表时间：
2008-06-24
影响因子：
11.1
作者：
Aygun, Ozan;Svejstrup, Jesper;Liu, Yilun
通讯作者：
Liu, Yilun
影响因子：
23.9
作者：
Ceccaldi, Raphael;Parmar, Kalindi;Mouly, Enguerran;Delord, Marc;Kim, Jung Min;Regairaz, Marie;Pla, Marika;Vasquez, Nadia;Zhang, Qing-Shuo;Pondarre, Corinne;de Latour, Regis Peffault;Gluckman, Eliane;Cavazzana-Calvo, Marina;Leblanc, Thierry;Larghero, Jerome;Grompe, Markus;Socie, Gerard;D'Andrea, Alan D.;Soulier, Jean
通讯作者：
Soulier, Jean