SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint.
SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint.
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DOI：
10.7554/elife.02482
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发表时间：
2014-05-06
期刊：
影响因子：
7.7
通讯作者：
de Almeida SF
中科院分区：
文献类型：
--
作者：
Carvalho S;Vítor AC;Sridhara SC;Martins FB;Raposo AC;Desterro JM;Ferreira J;de Almeida SF
组蛋白修饰建立了协调DNA损伤反应的染色质状态。在这项研究中，我们表明，SETD2，三甲基化组蛋白H3赖氨酸36（H3K36me3）的酶，需要ATM激活DNA双链断裂（DSB）。此外，我们发现，SETD2是必要的同源重组修复DSB通过促进形成的RAD 51突触前纤维。与此一致，SETD2突变型透明细胞肾细胞癌（ccRCC）细胞显示出受损的DNA损伤信号传导。然而，尽管DNA损伤持续存在，但SETD2缺陷细胞未能激活p53，这是基因组的主要监护人，在ccRCC中很少突变，并且在DNA损伤后显示细胞存活率降低。我们提出，这种新的依赖SETD 2的作用提供了一个染色质书签工具，促进信号和修复的DSB。在ccRCC中，SETD 2的缺失可以提供p53介导的检查点失活的替代机制，而不需要TP53中的额外基因突变。http://dx.doi.org/10.7554/eLife.02482.001正常的磨损、暴露于化学物质和紫外线都能损伤DNA，因此细胞依赖于一系列传感器和机制来检测和修复受损的DNA。细胞还将DNA分子包装在称为组蛋白的结构中，以保护它们免受损害。双链断裂是DNA损伤最严重的形式之一，它可以被一种叫做ATM的酶检测到，并可以通过两种方式修复。将断裂的链重新组合在一起是一个显而易见的方法，但它也容易出错。使用模板生成新的DNA来修复损伤不太容易出错，但它只能发生在细胞周期的某些时间。一些癌症与双链断裂的错误修复有关。此外，一种称为透明细胞肾癌的肾癌与一种称为p53的蛋白质缺乏活性有关，即使在这种蛋白质的基因没有突变的个体中也是如此。然而，许多患有这种类型癌症的人在一种称为SETD 2的蛋白质的基因中存在突变。为了研究SETD2和DNA修复之间的联系，Carvalho等人比较了有和没有SETD2基因突变的细胞。研究表明，DNA修复必须存在于SETD 2中：SETD 2修饰组蛋白，以便它们可以通过模板方法（相对无错误）招募修复DNA的酶。SETD 2对于修复基因损伤而不引入错误可能特别重要。Carvalho等人还表明，SETD2中的突变足以使p53失活。这种蛋白质的基因在大多数癌症中发生突变，它阻碍了具有基因组畸变（如双链断裂）的细胞的增殖。总的来说，这些结果有助于说明组蛋白修饰和DNA损伤修复机制以及检查点如何协同工作来抑制癌症。DOI：http://dx.doi.org/10.7554/eLife.02482.002网站
Histone modifications establish the chromatin states that coordinate the DNA damage response. In this study, we show that SETD2, the enzyme that trimethylates histone H3 lysine 36 (H3K36me3), is required for ATM activation upon DNA double-strand breaks (DSBs). Moreover, we find that SETD2 is necessary for homologous recombination repair of DSBs by promoting the formation of RAD51 presynaptic filaments. In agreement, SETD2-mutant clear cell renal cell carcinoma (ccRCC) cells displayed impaired DNA damage signaling. However, despite the persistence of DNA lesions, SETD2-deficient cells failed to activate p53, a master guardian of the genome rarely mutated in ccRCC and showed decreased cell survival after DNA damage. We propose that this novel SETD2-dependent role provides a chromatin bookmarking instrument that facilitates signaling and repair of DSBs. In ccRCC, loss of SETD2 may afford an alternative mechanism for the inactivation of the p53-mediated checkpoint without the need for additional genetic mutations in TP53. DOI: http://dx.doi.org/10.7554/eLife.02482.001 Normal wear and tear, exposure to chemicals, and ultraviolet light can all damage DNA, so cells rely on a range of sensors and mechanisms to detect and repair damaged DNA. Cells also package DNA molecules inside structures called histones to protect them against damage. Double-strand breaks—one of the most serious forms of DNA damage—are detected by an enzyme called ATM, and can be repaired in two ways. Bringing the broken strands back together is an obvious method, but it is also error prone. Using templates to generate new DNA to repair the damage is less prone to error, but it can only happen at certain times of the cell cycle. Some cancers are linked to the faulty repair of double-strand breaks. Moreover, a type of kidney cancer called clear cell renal carcinoma is linked to a lack of activity by a protein called p53, even in individuals who don't have mutations in the gene for this protein. However, many people with this type of cancer have mutations in the gene for a protein called SETD2. To investigate the links between SETD2 and DNA repair, Carvalho et al. compared cells with and without mutations in the gene for SETD2. It emerged that SETD2 must be present for DNA repair to take place: the SETD2 modifies the histones so that they can recruit the enzymes that repair the DNA via the template approach (which is relatively error free). SETD2 may be particularly important for repairing damage to genes without introducing errors. Carvalho et al. also show that mutations in SETD2 are sufficient to inactivate p53. The gene for this protein, which impedes the proliferation of cells with genomic aberrations, such as double-strand breaks, is mutated in most cancers. Overall the results help to illustrate how histone modifications and the DNA damage repair mechanisms and checkpoints work in concert to suppress cancer. DOI: http://dx.doi.org/10.7554/eLife.02482.002