Single-strand annealing between inverted DNA repeats: Pathway choice, participating proteins, and genome destabilizing consequences.
Single-strand annealing between inverted DNA repeats: Pathway choice, participating proteins, and genome destabilizing consequences.
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DOI：
10.1371/journal.pgen.1007543
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发表时间：
2018-08
期刊：
影响因子：
4.5
通讯作者：
Malkova A
中科院分区：
文献类型：
--
作者：
Ramakrishnan S;Kockler Z;Evans R;Downing BD;Malkova A
双链DNA断裂（DSB）是一种危险的事件，可能由各种原因引起，包括环境攻击或DNA复制的崩溃。虽然DSB的有效和精确修复对细胞存活至关重要，但错误的修复可能导致遗传不稳定，因此选择DSB修复是重要的一步。在这里，我们报告说，放置在DSB附近的反向DNA重复序列（IR）可以将其修复从导致基因转换的准确途径引导到导致遗传不稳定性的断裂诱导复制（BIR）途径。IR的作用是通过它们在存在于通过DSB切除形成的ssDNA中时形成不寻常的DNA结构的能力来解释的。我们证明，IR可以形成两种类型的不寻常的DNA结构，这些结构之间的选择取决于间隔区的长度分隔IR。特别是，由长（1-kb）间隔区分隔的IR主要参与分子间单链退火（SSA），导致形成反向二聚体;由短（12-bp）间隔区分隔的IR参与分子内SSA，导致形成折叠（FB）结构。这两种结构都通过基因转化干扰准确的DSB修复，并将DSB修复引导至BIR，这促进了基因组的不稳定。我们还报告说，不同的蛋白质复合物参与加工的FB含有短（12-bp）与长（1-kb）的ssDNA环。具体而言，短循环的FB由MRX-Sae 2复合体处理，而Rad 1-Rad 10复合体负责长循环的处理。总的来说，我们的研究揭示了由IR将DSB修复重新路由到不寻常的途径导致的基因组不稳定的机制。鉴于IR在人类基因组中的高丰度，我们的研究结果可能有助于理解与人类疾病相关的IR介导的基因组不稳定。由于细胞暴露于电离辐射或各种化学物质而导致的双链DNA断裂（DSB）的有效和准确修复对于细胞存活至关重要。相反，错误的DSB修复会产生基因组不稳定性，导致人类出生缺陷或癌症。在这里，我们证明了放置在DSB附近的反向DNA重复序列（IR），干扰DSB的准确修复，并促进基因组重排和染色体丢失。这是由位于不同DNA分子或同一分子中的反向重复序列之间的退火引起的。此外，我们描述了一个新的作用，Rad 1-Rad 10蛋白复合物在处理折叠回（FB）结构形成的分子内退火涉及IR分离的长间隔。相比之下，具有短间隔区的FB由Mre 11-Rad 50-Xrs 2/-Sae 2复合物加工。总的来说，我们描述了几种途径的DSB促进IR之间的相互作用，可以导致基因组的不稳定性。鉴于人类基因组中存在大量IR，我们的发现与导致人类基因组不稳定从而导致癌症和其他疾病发生的机制相关。
Double strand DNA breaks (DSBs) are dangerous events that can result from various causes including environmental assaults or the collapse of DNA replication. While the efficient and precise repair of DSBs is essential for cell survival, faulty repair can lead to genetic instability, making the choice of DSB repair an important step. Here we report that inverted DNA repeats (IRs) placed near a DSB can channel its repair from an accurate pathway that leads to gene conversion to instead a break-induced replication (BIR) pathway that leads to genetic instabilities. The effect of IRs is explained by their ability to form unusual DNA structures when present in ssDNA that is formed by DSB resection. We demonstrate that IRs can form two types of unusual DNA structures, and the choice between these structures depends on the length of the spacer separating IRs. In particular, IRs separated by a long (1-kb) spacer are predominantly involved in inter-molecular single-strand annealing (SSA) leading to the formation of inverted dimers; IRs separated by a short (12-bp) spacer participate in intra-molecular SSA, leading to the formation of fold-back (FB) structures. Both of these structures interfere with an accurate DSB repair by gene conversion and channel DSB repair into BIR, which promotes genomic destabilization. We also report that different protein complexes participate in the processing of FBs containing short (12-bp) versus long (1-kb) ssDNA loops. Specifically, FBs with short loops are processed by the MRX-Sae2 complex, whereas the Rad1-Rad10 complex is responsible for the processing of long loops. Overall, our studies uncover the mechanisms of genomic destabilization resulting from re-routing DSB repair into unusual pathways by IRs. Given the high abundance of IRs in the human genome, our findings may contribute to the understanding of IR-mediated genomic destabilization associated with human disease. Efficient and accurate repair of double-strand DNA breaks (DSBs), resulting from the exposure of cells to ionizing radiation or various chemicals, is crucial for cell survival. Conversely, faulty DSB repair can generate genomic instability that can lead to birth defects or cancer in humans. Here we demonstrate that inverted DNA repeats (IRs) placed in the vicinity of a DSB, interfere with the accurate repair of DSBs and promote genomic rearrangements and chromosome loss. This results from annealing between inverted repeats, located either in different DNA molecules or in the same molecule. In addition, we describe a new role for the Rad1-Rad10 protein complex in processing fold-back (FB) structures formed by intra-molecular annealing involving IRs separated by long spacers. In contrast, FBs with short spacers are processed by the Mre11-Rad50-Xrs2/-Sae2 complex. Overall, we describe several pathways of DSB promoted interaction between IRs that can lead to genomic instability. Given the large number of IRs in the human genome, our findings are relevant to the mechanisms driving genomic destabilization in humans contributing to the development of cancer and other diseases.
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使用基于ALU元素的不稳定性模型比较100个人类基因。
影响因子：
3.7
作者：
Cook GW;Konkel MK;Walker JA;Bourgeois MG;Fullerton ML;Fussell JT;Herbold HD;Batzer MA
通讯作者：
Batzer MA
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1016/j.mrfmmm.2008.07.013
发表时间：
2008-10-14
影响因子：
2.3
作者：
Downing, Brandon;Morgan, Rachel;Malkova, Anna
通讯作者：
Malkova, Anna
影响因子：
64.5
作者：
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通讯作者：
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