[SAMHD1 acts at stalled replication forks to prevent interferon induction].
[SAMHD1 acts at stalled replication forks to prevent interferon induction].
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DOI：
10.5802/crbiol.10
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发表时间：
2020-06
影响因子：
2
通讯作者：
Flavie Coquel;M. J. Silva;H. Técher;Karina Zadorozhny;Sushma Sharma;J. Nieminuszczy;C. Mettling;E. Dardillac;Antoine Barthe;Anne-Lyne Schmitz;Alexy Promonet;Alexandra Cribier;Amélie Sarrazin;W. Niedzwiedz;B. Lopez;V. Costanzo;L. Krejci;A. Chabes;M. Benkirane;Yea-Lih Lin;P. Pasero
中科院分区：
文献类型：
--
作者：
Flavie Coquel;M. J. Silva;H. Técher;Karina Zadorozhny;Sushma Sharma;J. Nieminuszczy;C. Mettling;E. Dardillac;Antoine Barthe;Anne-Lyne Schmitz;Alexy Promonet;Alexandra Cribier;Amélie Sarrazin;W. Niedzwiedz;B. Lopez;V. Costanzo;L. Krejci;A. Chabes;M. Benkirane;Yea-Lih Lin;P. Pasero
DNA复制是一个极其复杂的过程，涉及到成千上万的复制叉沿沿着染色体前进。这些分叉经常被各种障碍物减缓或停止，例如二级DNA结构，染色质作用蛋白或缺乏核苷酸。这种减缓，被称为复制应激，在肿瘤发展中起着核心作用。尚未完全理解的复杂过程是为了应对这种压力而建立的。某些核酸酶，如MRE 11和DNA 2，在阻断的叉水平上降解新复制的DNA，允许复制重新开始。干扰素途径是针对病原体的防御机制，其检测细胞质中外源核酸的存在并激活先天免疫应答。由基因组DNA代谢（修复、反转录转座）产生的DNA片段可以扩散到细胞质中并激活该途径。这一过程的病理表现是Aicardi-Goutières综合征，这是一种罕见的疾病，其特征是慢性炎症，导致神经退行性和发育问题。在这种脑病中，有人认为DNA复制可能产生胞质DNA片段，但涉及的机制尚未确定。SAMHD 1在Aicardi-Goutières综合征和一些癌症中经常发生突变，但其在这些疾病的病因学中的作用在很大程度上是未知的。我们发现，胞浆DNA积累在SAMHD 1缺陷的细胞，特别是在复制应激的存在下，激活干扰素反应。SAMHD 1对于正常条件下的DNA复制和停止叉的加工是重要的，与其dNTR活性无关。此外，SAMHD 1在体外刺激MRE 11的核酸外切酶活性。当SAMHD 1不存在时，新合成的DNA的降解被抑制，这阻止了复制检查点的激活并导致复制叉重新启动失败。复制叉的切除是通过另一种机制进行的，该机制将DNA片段释放到胞质溶胶中，激活干扰素反应。所获得的结果表明，第一次，复制应力和干扰素的生产之间的直接联系的反应。这些结果对我们理解Aicardi-Goutières综合征和SAMHD 1相关癌症具有重要意义。例如，我们已经证明MRE 11和RECQ 1负责产生DNA片段，这些片段在缺乏SAMHD 1的细胞中引发炎症反应。因此，我们可以想象，阻断这些酶的活性可以减少DNA片段的产生，并最终激活这些细胞中的先天免疫。此外，干扰素途径在辐射和某些化疗剂如奥沙利铂的治疗功效中起重要作用。因此，调节这种反应可能在抗肿瘤治疗中具有更广泛的意义。
DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are frequently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. This slowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutières syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not been characterized. SAMHD1 is frequently mutated in the Aicardi-Goutières syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutières syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy.