The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair.
The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair.
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DOI：
10.1016/j.dnarep.2014.07.007
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发表时间：
2014-10
期刊：
影响因子：
3.8
通讯作者：
Bernstein KA
中科院分区：
文献类型：
--
作者：
Böhm S;Bernstein KA
RecQ样解旋酶是一个高度保守的蛋白质家族，对于保持基因组完整性至关重要。基因组不稳定性被认为是癌症的标志，五个人类RECQ基因中的三个突变会导致与癌症易感性相关的遗传综合征。人RecQ样解旋酶BLM在DNA损伤信号传导、修复、复制和端粒维持中具有中心作用。BLM及其芽殖酵母同源物Sgs 1解旋双链DNA中间体。有趣的是，BLM在复制损伤后以亲和反重组发生的方式起作用，作用于相似的底物。因此，必须复杂地控制BLM活性，以防止可能对基因组完整性产生有害影响的非法重组事件。近年来，很明显，BLM的翻译后修饰（PTM）可以对其功能进行微调。到目前为止，BLM磷酸化，泛素化和SUMO化已被确定，反过来又调节其亚细胞定位，蛋白质-蛋白质相互作用和蛋白质稳定性。在这篇综述中，我们将讨论这些不同的修改BLM发生的时间和方式的细胞背景。我们将反映目前的模型如何PTM控制BLM功能在DNA损伤修复和比较这是什么已知的芽殖酵母直向同源物SGS 1的翻译后调控。最后，我们将对未来的研究进行展望，特别是剖析BLM上各个PTM之间的串扰。
RecQ-like helicases are a highly conserved family of proteins which are critical for preserving genome integrity. Genome instability is considered a hallmark of cancer and mutations within three of the five human RECQ genes cause hereditary syndromes that are associated with cancer predisposition. The human RecQ-like helicase BLM has a central role in DNA damage signaling, repair, replication, and telomere maintenance. BLM and its budding yeast orthologue Sgs1 unwind double-stranded DNA intermediates. Intriguingly, BLM functions in both a pro- and anti-recombinogenic manner upon replicative damage, acting on similar substrates. Thus, BLM activity must be intricately controlled to prevent illegitimate recombination events that could have detrimental effects on genome integrity. In recent years it has become evident that post-translational modifications (PTMs) of BLM allow a fine-tuning of its function. To date, BLM phosphorylation, ubiquitination, and SUMOylation have been identified, in turn regulating its subcellular localization, protein-protein interactions, and protein stability. In this review, we will discuss the cellular context of when and how these different modifications of BLM occur. We will reflect on the current model of how PTMs control BLM function during DNA damage repair and compare this to what is known about post-translational regulation of the budding yeast orthologue Sgs1. Finally, we will provide an outlook towards future research, in particular to dissect the cross-talk between the individual PTMs on BLM.
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