BACKGROUND & AIMS: :The genotoxic activity of 11 mycotoxins was investigated in Escherichia coli K 12. The induction of the SOS function sfi A whose level of expression is monitored by means of a sfi A::lac Z operon fusion was assayed by measuring the beta-galactosidase activity in the PQ 37 strain. Most of these fungal metabolites did not induce SOS response in this bacterial test. Only aflatoxicol, a reduced metabolite of aflatoxin B1 was well detected as an SOS inducer if metabolic activation was performed. Patulin, penicillic acid and viomellein are only weak inducing agents. The other fungal compounds tested failed to demonstrate a positive SOS inducing activity. Relationship between SOS chromotest, mutagenicity to Salmonella typhimurium and in vivo carcinogenicity was discussed.

背景与目标： ：在大肠杆菌K 12中研究了11种霉菌毒素的遗传毒性活性。通过测量β-半乳糖苷酶活性来测定SOS功能sfi A的诱导，其表达水平通过sfi A :: lac Z操纵子融合体进行监测在PQ 37株中。这些真菌代谢物中的大多数在此细菌测试中均未诱导SOS反应。如果进行了代谢激活，则只有黄曲霉酚（一种降低的黄曲霉毒素B1代谢产物）可以作为SOS诱导剂被很好地检测到。棒曲霉素，青霉酸和堇青素仅是弱诱导剂。测试的其他真菌化合物未能显示出积极的SOS诱导活性。讨论了SOS显色性，对鼠伤寒沙门氏菌的致突变性与体内致癌性之间的关系。

BACKGROUND & AIMS: :The SOS Chromotest on Escherichia coli strain PQ37 was used to detect DNA damage induced by 16 chemical compounds and urine samples from smokers and a non-smoking psoriatic patient treated with mineral coal tar. The results confirmed the strong SOS inducing activity of 2-aminoanthracene and benzo[a]pyrene with metabolic activation and N-methyl-N'-nitro-N-nitrosoguanidine, mitomycin C and 4-nitroquinoline-N-oxide without metabolic activation. A weaker response in the absence of microsomal enzymes was observed with hydroxyurea (only at high doses) and the soluble Cr(VI) compounds potassium chromate and potassium dichromate. No effect was observed with ampicillin, cadmium chloride, cyclophosphamide, griseofulvin, the insoluble Cr(VI) compound lead chromate, the soluble Cr(III) compounds chromium nitrate, chromium chloride, chromium potassium sulphate, and the chelating agent sodium nitrilotriacetate. Among the Cr(III) compounds only chromium acetate produced a low but significant increase of SOS inducing activity. Solubilization by nitrilotriacetate of genotoxic Cr(VI) from insoluble lead chromate was observed, whereas no interaction occurred between nitrilotriacetate and the soluble Cr(VI) and Cr(III) compounds. Using urinary XAD-2 extracts, we found the SOS Chromotest poorly sensitive to the mutagens present in urine from tobacco smokers which, on the other hand, were detected by the gene mutation assay in Salmonella typhimurium (Ames test). A urine sample obtained from a psoriatic patient, therapeutically treated with mineral coal tar, had a significant SOS inducing activity with and even without metabolic activation, whereas in the Ames test it was active only in the presence of metabolic activation.(ABSTRACT TRUNCATED AT 250 WORDS)

背景与目标： ：使用SOS Chromotest对大肠杆菌PQ37菌株进行检测，以检测由16种化合物和吸烟者以及一名接受矿物煤焦油治疗的非吸烟性银屑病患者的尿液样品引起的DNA损伤。该结果证实了具有2-甲基蒽和苯并[a] py具有代谢活化和没有代谢活化的N-甲基-N'-硝基-N-亚硝基胍，丝裂霉素C和4-硝基喹啉-N-氧化物的强SOS诱导活性。使用羟基脲（仅在高剂量时）和可溶性Cr（VI）化合物铬酸钾和重铬酸钾观察到在不存在微粒体酶的情况下响应较弱。氨苄青霉素，氯化镉，环磷酰胺，灰黄霉素，不溶性Cr（VI）化合物铬酸铅，可溶性Cr（III）化合物硝酸铬，氯化铬，硫酸铬钾和螯合剂次氮基三乙酸钠未见效果。在Cr（III）化合物中，只有乙酸铬产生的SOS诱导活性低但显着增加。观察到次氮基三乙酸盐从不溶的铬酸铅中溶解了具有遗传毒性的Cr（VI），而次氮基三乙酸盐与可溶性Cr（VI）和Cr（III）化合物之间未发生相互作用。使用尿液XAD-2提取物，我们发现SOS Chromotest对吸烟者尿液中存在的诱变剂不敏感，而另一方面，通过鼠伤寒沙门氏菌的基因突变检测（Ames试验）检测到了。从银屑病患者接受矿物煤焦油治疗的尿液样品在有或没有代谢活化的情况下均具有显着的SOS诱导活性，而在Ames试验中，它仅在存在代谢活化的情况下才具有活性。（摘要摘录于250字）

BACKGROUND & AIMS: :The SOS response is readily triggered by replication fork stalling caused by DNA damage or a dysfunctional replicative apparatus in Escherichia coli cells. E. coli dinB encodes DinB DNA polymerase and its expression is upregulated during the SOS response. DinB catalyzes translesion DNA synthesis in place of a replicative DNA polymerase III that is stalled at a DNA lesion. We showed previously that DNA replication was suppressed without exogenous DNA damage in cells overproducing DinB. In this report, we confirm that this was due to a dose-dependent inhibition of ongoing replication forks by DinB. Interestingly, the DinB-overproducing cells did not significantly induce the SOS response even though DNA replication was perturbed. RecA protein is activated by forming a nucleoprotein filament with single-stranded DNA, which leads to the onset of the SOS response. In the DinB-overproducing cells, RecA was not activated to induce the SOS response. However, the SOS response was observed after heat-inducible activation in strain recA441 (encoding a temperature-sensitive RecA) and after replication blockage in strain dnaE486 (encoding a temperature-sensitive catalytic subunit of the replicative DNA polymerase III) at a non-permissive temperature when DinB was overproduced in these cells. Furthermore, since catalytically inactive DinB could avoid the SOS response to a DinB-promoted fork block, it is unlikely that overproduced DinB takes control of primer extension and thus limits single-stranded DNA. These observations suggest that DinB possesses a feature that suppresses DNA replication but does not abolish the cell's capacity to induce the SOS response. We conclude that DinB impedes replication fork progression in a way that does not activate RecA, in contrast to obstructive DNA lesions and dysfunctional replication machinery.

背景与目标： ：SOS响应很容易因DNA损伤或大肠杆菌细胞复制装置功能异常而引起的复制叉停转而触发。大肠杆菌dinB编码DinB DNA聚合酶，并且在SOS反应期间其表达上调。 DinB可以催化停滞在DNA病变处的复制型DNA聚合酶III，从而催化跨病变的DNA合成。我们以前表明，在过量生产DinB的细胞中，DNA复制被抑制而没有外源DNA损伤。在此报告中，我们确认这是由于DinB对正在进行的复制叉的剂量依赖性抑制。有趣的是，即使DNA复制受到干扰，DinB过量产生细胞也不会显着诱导SOS反应。 RecA蛋白通过形成具有单链DNA的核蛋白丝而被激活，从而导致SOS反应的发生。在过量产生DinB的细胞中，RecA没有被激活以诱导SOS反应。但是，在菌株recA441中的热诱导激活（编码温度敏感的RecA）之后和在菌株dnaE486中的复制受阻（编码复制性DNA聚合酶III的温度敏感催化亚基）非允许的情况下，观察到了SOS反应。 DinB在这些细胞中过量产生时的温度。此外，由于具有催化活性的DinB可以避免SOS对DinB促进的叉叉反应的应答，因此过量生产的DinB不太可能控制引物延伸并因此限制了单链DNA。这些观察结果表明，DinB具有抑制DNA复制但不会消除细胞诱导SOS反应的能力的功能。我们得出的结论是，与阻塞性DNA损伤和功能障碍的复制机制相反，DinB以不激活RecA的方式阻碍了复制叉的发展。

BACKGROUND & AIMS: :Four nitroarenes were tested in two standard genotoxicity assay systems using three well-known bacterial tester strains. The results were as follows: 4-nitroquinoline l-oxide (4NQO) was positive in Quillardet and Hofnung's SOS chromotest using Escherichia coli strain PQ37 both in the presence and absence of microsomal (S9) supplements and in the Salmonella typhimurium umu tester strains NM2009 and NM3009, which express high levels of O-acetyltransferase (O-AT) and O-AT plus nitroreductase (NR) respectively. m-Nitrocinnamic acid (m-NCA) was weakly positive in strains NM2009 and NM3009, but negative in the SOS chromotest; m-dinitrobenzene (m-DNB) was weakly positive in strain NM2009, intermediate positive in strain NM3009, but negative in the SOS chromotest; 2,4-dinitrotoluene (2,4-DNT) was weakly positive in strain NM3009, but negative in strain NM2009 and in the SOS chromotest. However it still showed a dose-response relationship in strain NM2009. In view of these results, it is suggested that investigators planning to screen miscellaneous nitroarenes for their genotoxicity in the future should consider taking advantage of the increased sensitivity which is conferred on S. typhimurium strains NM2009 and NM3009 by virtue of their capacity to overexpress O-AT or O-AT and NR.

背景与目标： 在四个标准的遗传毒性测定系统中，使用三种著名的细菌测试菌株对四个硝基芳烃进行了测试。结果如下：在存在和不存在微粒体（S9）补充剂和鼠伤寒沙门氏菌UM2009测试株中，使用大肠杆菌PQ37菌株在Quillardet和Hofnung的SOS色度测试中，4-硝基喹啉L-氧化物（4NQO）呈阳性。 NM3009，分别表达高水平的O-乙酰基转移酶（O-AT）和O-AT加硝基还原酶（NR）。间硝基肉桂酸（m-NCA）在NM2009和NM3009菌株中呈弱阳性，但在SOS色度测试中呈阴性。间二硝基苯（m-DNB）在NM2009菌株中呈弱阳性，在NM3009菌株中呈中等阳性，但在SOS色度测试中呈阴性。 2,4-二硝基甲苯（2,4-DNT）在NM3009菌株中呈弱阳性，而在NM2009菌株和SOS色度试验中呈阴性。然而，它仍然显示出菌株NM2009中的剂量反应关系。鉴于这些结果，建议研究人员计划将来筛选其他硝基芳烃的遗传毒性，应考虑利用鼠伤寒沙门氏菌菌株NM2009和NM3009的敏感性增强，因为它们具有过表达O-的能力。 AT或O-AT和NR。

BACKGROUND & AIMS: :The 6C RNA family is a class of small RNAs highly conserved in Actinobacteria, including the genera Mycobacterium, Streptomyces and Corynebacterium whose physiological function has not yet been elucidated. We found that strong transcription of the cgb_03605 gene, which encodes 6C RNA in C. glutamicum, was driven by the SigA- and SigB-dependent promoter Pcgb_03605. 6C RNA was detected at high level during exponential growth phase (180 to 240 molcules per cell) which even increased at the entry of the stationary phase. 6C RNA level did not decrease within 240 min after transcription had been stopped with rifampicin, which suggests high 6C RNA stability. The expression of cgb_03605 further increased approximately twofold in the presence of DNA-damaging mitomycin C (MMC) and nearly threefold in the absence of LexA. Deletion of the 6C RNA gene cgb_03605 resulted in a higher sensitivity of C. glutamicum toward MMC and UV radiation. These results indicate that 6C RNA is involved in the DNA damage response. Both 6C RNA level-dependent pausing of cell growth and branched cell morphology in response to MMC suggest that 6C RNA may also be involved in a control of cell division.

背景与目标： ：6C RNA家族是放线菌中高度保守的一类小RNA，包括尚未阐明其生理功能的分枝杆菌属，链霉菌属和棒状杆菌属。我们发现，由SigA和SigB依赖性启动子Pcgb_03605驱动cgb_03605基因的强转录，该基因在谷氨酸棒杆菌中编码6C RNA。在指数生长期（每个细胞180到240分子），高水平检测到6C RNA，甚至在固定相进入时也增加。用利福平终止转录后240分钟内6C RNA水平没有降低，这表明6C RNA的稳定性很高。在存在破坏DNA的丝裂霉素C（MMC）的情况下，cgb_03605的表达进一步增加了约两倍，而在不存在LexA的情况下，其表达则增加了近三倍。 6C RNA基因cgb_03605的删除导致谷氨酸棒杆菌对MMC和UV辐射的敏感性更高。这些结果表明6C RNA参与了DNA损伤反应。响应MMC的6C RNA水平依赖性细胞生长暂停和分支细胞形态均表明6C RNA也可能参与细胞分裂的控制。

BACKGROUND & AIMS: To examine the concordance of two microbial genotoxicity short-term assays, 330 experimental results for the SOS chromotest using tester strain Escherichia coli PQ37 were compared with the results of the Salmonella/mammalian microsome mutagenicity assay with Salmonella typhimurium TA97, TA98, TA100, TA102, TA104, TA1535, TA1537 and/or TA1538. With respect to qualitative features, the concordance between SOS chromotest and Salmonella mutagenicity test results was 86.4% (sensitivity, 78.6%; specificity, 100%; chi 2 = 188.6). None of the non-mutagens (N = 120) were able to induce the SOS system. Additionally, 45 of the 210 S.typhimurium mutagens (21.5%) did not induce the SOS repair system. On closer examination, the majority of these 45 compounds (84%) were mutagens with activities between 0.001 and 10 rev/nmol. Even though the experimental protocols of both systems were not standardized, the correlation coefficient for the experimental results of the two test systems was 0.7 for the 330 chemicals. Except for aliphatic epoxides (r = 0.47), the mutagenicity/SOS induction correlations for congeneric data sets (polycyclic aromatic hydrocarbons, nitroarenes, nitroarenofurans, mycotins) were even better (r = 0.72-0.95). Additionally, computer automated structure evaluation (CASE) analyses of the nature of the structural determinants associated with each endpoint indicate extensive homologies. The data can be taken to indicate that the two phenomena reflect common mechanisms of action.

背景与目标： 为了检验两种微生物遗传毒性短期测定的一致性，将330例使用测试菌株Escherichia coli PQ37进行SOS色度测试的实验结果与采用鼠伤寒沙门氏菌TA97，TA98，TA100，TA102， TA104，TA1535，TA1537和/或TA1538。就定性特征而言，SOS色度测试与沙门氏菌诱变测试结果之间的一致性为86.4％（敏感性为78.6％；特异性为100％； chi 2 = 188.6）。所有非突变体（N = 120）均无法诱导SOS系统。此外，210个鼠伤寒沙门氏菌中有45个（21.5％）没有诱导SOS修复系统。经仔细检查，这45种化合物中的大多数（84％）是诱变剂，其活性在0.001和10 rev / nmol之间。即使两个系统的实验方案均未标准化，但对于330种化学品，两个测试系统的实验结果的相关系数均为0.7。除脂族环氧化物（r = 0.47）外，同类数据集（多环芳烃，硝基芳烃，硝基芳呋喃，霉菌毒素）的诱变性/ SOS诱导相关性甚至更好（r = 0.72-0.95）。此外，与每个端点关联的结构决定因素的性质的计算机自动结构评估（CASE）分析表明，存在广泛的同源性。可以得出的数据表明这两种现象反映了共同的作用机理。

BACKGROUND & AIMS: :Quinolone antibacterial drugs such as nalidixic acid target DNA gyrase in Escherichia coli. These inhibitors bind to and stabilize a normally transient covalent protein-DNA intermediate in the gyrase reaction cycle, referred to as the cleavage complex. Stabilization of the cleavage complex is necessary but not sufficient for cell killing--cytotoxicity apparently results from the conversion of cleavage complexes into overt DNA breaks by an as-yet-unknown mechanism(s). Quinolone treatment induces the bacterial SOS response in a RecBC-dependent manner, arguing that cleavage complexes are somehow converted into double-stranded breaks. However, the only proteins known to be required for SOS induction by nalidixic acid are RecA and RecBC. In hopes of identifying additional proteins involved in the cytotoxic response to nalidixic acid, we screened for E. coli mutants specifically deficient in SOS induction upon nalidixic acid treatment by using a dinD::lacZ reporter construct. From a collection of SOS partially constitutive mutants with disruptions of 47 different genes, we found that dnaQ insertion mutants are specifically deficient in the SOS response to nalidixic acid. dnaQ encodes DNA polymerase III epsilon subunit, the proofreading subunit of the replicative polymerase. The deficient response to nalidixic acid was rescued by the presence of the wild-type dnaQ gene, confirming involvement of the epsilon subunit. To further characterize the SOS deficiency of dnaQ mutants, we analyzed the expression of several additional SOS genes in response to nalidixic acid using real-time PCR. A subset of SOS genes lost their response to nalidixic acid in the dnaQ mutant strain, while two tested SOS genes (recA and recN) continued to exhibit induction. These results argue that the replication complex plays a role in modulating the SOS response to nalidixic acid and that the response is more complex than a simple on/off switch.

背景与目标： ：喹诺酮类抗菌药物，例如萘啶酸可靶向大肠杆菌中的DNA促旋酶。这些抑制剂在促旋酶反应周期中结合并稳定通常短暂的共价蛋白-DNA中间体，称为裂解复合物。裂解复合物的稳定对于杀死细胞是必要的，但还不足以使细胞毒性-细胞毒性显然是由于裂解复合物通过迄今未知的机制转化为明显的DNA断裂所致。喹诺酮治疗以RecBC依赖的方式诱导细菌SOS反应，认为裂解复合物以某种方式转化为双链断裂。但是，已知萘啶酸诱导SOS所需的唯一蛋白质是RecA和RecBC。为了希望鉴定涉及对萘啶酸的细胞毒性反应的其他蛋白质，我们使用dinD :: lacZ报告基因构建体筛选了在萘啶酸处理后特异缺乏SOS诱导作用的大肠杆菌突变体。从具有47个不同基因破坏的SOS部分组成性突变体的集合中，我们发现dnaQ插入突变体在SOS对萘啶酸的反应中特别缺乏。 dnaQ编码DNA聚合酶IIIε亚基，即复制性聚合酶的校对亚基。野生型dnaQ基因的存在挽救了对萘啶酸的不足反应，证实了ε亚基的参与。为了进一步表征dnaQ突变体的SOS缺陷，我们使用实时PCR分析了响应于萘啶酸的一些其他SOS基因的表达。 SOS基因的一个子集在dnaQ突变菌株中失去了对萘啶酸的反应，而两个测试的SOS基因（recA和recN）继续表现出诱导作用。这些结果表明复制复合物在调节SOS对萘啶酸的反应中起作用，并且该反应比简单的开/关开关更复杂。

BACKGROUND & AIMS: UV-inducible precise excision of transposons is a specific SOS-mutagenesis process. It deals with the deletion formation which has previously been demonstrated to involve direct or inverted IS-sequences of transposons. The process was used for revisiting the targeted and untargeted SOS-mutability and its relationship to the key genes for SOS-mutagenesisthe recA, lexA and umuDC. The precise excision of transposons Tn5 and Tn10 from the chromosomal insertion sites ade128 and cyc750 is induced in Escherichia coli K-12 and B cells, wild-type for DNA-repair, both by the low doses of UV-light ranging from 0.25 J m-2 to 2.5 J m-2 and the high doses within the range 5.0-40.0 J m-2. Precise excision of these transposons induced by the range of low doses incapable to induce targeted point mutations reveals its mostly untargeted nature. This process for the transposon Tn1 is not induced by UV-light within the range of doses 0.25-2.5 J m-2 while its induction is possible by UV-fluences ranging from 5.0 to 40.0 J m-2. A dose-response of the precise excision of Tn1 is similar to that of the UV-induced reversion of trpUAA point mutation that is targeted by nature and contrasts to the UV-inducible precise excision of Tn5 and Tn10. Both types of UV-inducible precise excision, demonstrated either by Tn1 or Tn5 and Tn10, are eliminated by mutations in the lexA, recA and umuDC genes indispensable for UV-induced SOS-mutability. The palindromic structures different for the transposons Tn1, Tn5 and Tn10 are discussed to be involved and affect the targeted and untargeted precise excision of transposons induced by UV-light.

背景与目标： 紫外线诱导的转座子的精确切除是一个特定的SOS诱变过程。它处理先前已经证明涉及转座子的直接或反向IS序列的缺失形成。该过程用于重新研究有针对性和无针对性的SOS突变性及其与SOS突变关键基因的关系，即recA，lexA和umuDC。大肠杆菌K-12和B细胞（DNA修复的野生型）可诱导从染色体插入位点ade128和cyc750上精确除去转座子Tn5和Tn10，二者均通过低剂量的0.25 J m的紫外线照射-2至2.5 J m-2，高剂量在5.0-40.0 J m-2范围内。这些转座子的精确切除是由不能诱导靶点突变的低剂量范围引起的，揭示了它的大部分是非靶向性质。在剂量0.25-2.5 J m-2的范围内，紫外线不会诱导转座子Tn1的这一过程，而在5.0至40.0 J m-2的UV通量下，它的诱导是可能的。 Tn1精确切除的剂量反应类似于自然界靶向的UV诱导的trpUAA点突变回复，与紫外线诱导的Tn5和Tn10精确切除形成对比。通过Tn1或Tn5和Tn10证明的两种类型的紫外线诱导精确切除都可以通过lexA，recA和umuDC基因中的突变消除，而lexA，recA和umuDC基因对于紫外线诱导的SOS变异性是必不可少的。讨论了涉及转座子Tn1，Tn5和Tn10的回文结构，这些结构会影响UV光诱导的转座子的靶向和非靶向精确切除。

BACKGROUND & AIMS: :The alleviation of DNA restriction during the SOS response in Escherichia coli has been further investigated. With the EcoK DNA restriction system UV irradiated wild-type cells show a 10(4)-fold increase in ability to plate non-modified lambda phage and a 3-4 fold increase in transformation by non-modified plasmid DNA. A role for the umuDC genes of E coli in the process of SOS-induced restriction alleviation was identified by showing that a umuC122::Tn5 mutant could alleviate EcoK restriction to only 5% that of wild-type levels. Although umuDC are better characterized for their pivotal role in SOS induced mutagenesis, it is demonstrated here that umu-dependent alleviation of EcoK restriction is a transient process in which umu-dependent mutagenesis plays little part. A second form of SOS induced alleviation of DNA restriction is described in this paper involving the McrA restriction system. The mcrA gene is shown to be encoded within a defective prophage called e14 situated at the 25 min region on the Escherichia coli genetic map. e14 is known to abortively excise from the chromosome after SOS induction and it is demonstrated in this report that mcrA is lost from the genome after SOS induction as part of e14. This results in co-ordinate decrease in the level of McrA restriction within a population of cells.

背景与目标： ：进一步研究了在大肠杆菌中SOS反应过程中DNA限制的减轻。使用EcoK DNA限制系统，紫外线照射的野生型细胞显示出接种未修饰的λ噬菌体的能力提高了10（4）倍，而未修饰的质粒DNA的转化率则提高了3-4倍。通过显示umuC122 :: Tn5突变体可以将EcoK限制降低到野生型水平的5％，从而确定了大肠杆菌的umuDC基因在SOS诱导的限制减轻过程中的作用。尽管umuDC因其在SOS诱变中的关键作用而得到了更好的表征，但在此证明了umu依赖性对EcoK限制的缓解是一个瞬态过程，其中umu依赖性诱变起着很小的作用。本文介绍了SOS诱导减轻DNA限制的第二种形式，涉及McrA限制系统。已显示mcrA基因被编码在大肠杆菌遗传图谱中位于25分钟区域的称为e14的缺陷前噬菌体中。已知e14在SOS诱导后从染色体上流产地切除，并且在本报告中证明，作为e14的一部分，在SOS诱导后mcrA从基因组中丢失。这导致细胞群中Mcrr限制水平的坐标降低。

BACKGROUND & AIMS: :SOS1 and SOS2 are the most universal and widely expressed family of guanine exchange factors (GEFs) capable or activating RAS or RAC1 proteins in metazoan cells. SOS proteins contain a sequence of modular domains that are responsible for different intramolecular and intermolecular interactions modulating mechanisms of self-inhibition, allosteric activation and intracellular homeostasis. Despite their homology, analyses of SOS1/2-KO mice demonstrate functional prevalence of SOS1 over SOS2 in cellular processes including proliferation, migration, inflammation or maintenance of intracellular redox homeostasis, although some functional redundancy cannot be excluded, particularly at the organismal level. Specific SOS1 gain-of-function mutations have been identified in inherited RASopathies and various sporadic human cancers. SOS1 depletion reduces tumorigenesis mediated by RAS or RAC1 in mouse models and is associated with increased intracellular oxidative stress and mitochondrial dysfunction. Since WT RAS is essential for development of RAS-mutant tumors, the SOS GEFs may be considered as relevant biomarkers or therapy targets in RAS-dependent cancers. Inhibitors blocking SOS expression, intrinsic GEF activity, or productive SOS protein-protein interactions with cellular regulators and/or RAS/RAC targets have been recently developed and shown preclinical and clinical effectiveness blocking aberrant RAS signaling in RAS-driven and RTK-driven tumors.

背景与目标： ：SOS1和SOS2是最普遍和广泛表达的鸟嘌呤交换因子（GEF）家族，能够或激活后生动物细胞中的RAS或RAC1蛋白。 SOS蛋白包含一系列模块化结构域，这些结构域负责调节分子内和分子间的相互作用，从而调节自我抑制，变构激活和细胞内稳态。尽管它们具有同源性，但对SOS1 / 2-KO小鼠的分析显示，在细胞过程中SOS1在功能上普遍高于SOS2，包括增殖，迁移，炎症或细胞内氧化还原稳态的维持，尽管不能排除某些功能冗余，特别是在机体水平上。在遗传的RASopathies和各种散发性人类癌症中，已经确定了特定的SOS1功能获得性突变。 SOS1耗竭减少小鼠模型中由RAS或RAC1介导的肿瘤发生，并与细胞内氧化应激增加和线粒体功能障碍有关。由于WT RAS对于RAS突变肿瘤的发展必不可少，因此SOS GEF可被视为RAS依赖型癌症中的相关生物标志物或治疗靶标。最近已经开发了抑制SOS表达，内在GEF活性或生产性SOS蛋白-蛋白与细胞调节剂和/或RAS / RAC靶标相互作用的抑制剂，这些抑制剂在临床上和临床上均有效地阻断了RAS驱动和RTK驱动的肿瘤中异常RAS信号传导。

BACKGROUND & AIMS: :Small oxoacids of sulfur (SOS) are elusive molecules like sulfenic acid, HSOH, and sulfinic acid, HS(O)OH, generated during the oxidation of hydrogen sulfide, H2S, in aqueous solution. Unlike their alkyl homologs, there is a little data on their generation and speciation during H2S oxidation. These SOS may exhibit both nucleophilic and electrophilic reactivity, which we attribute to interconversion between S(II) and S(IV) tautomers. We find that SOS may be trapped in situ by derivatization with nucleophilic and electrophilic trapping agents and then characterized by high resolution LC MS. In this report, we compare SOS formation from H2S oxidation by a variety of biologically relevant oxidants. These SOS appear relatively long lived in aqueous solution, and thus may be involved in the observed physiological effects of H2S.

背景与目标： ：硫的少量含氧酸（SOS）是难以捉摸的分子，例如亚硫酸，HSOH和亚硫酸HS（O）OH，它们是在水溶液中硫化氢H2S氧化过程中产生的。与它们的烷基同系物不同，关于硫化氢氧化过程中它们的生成和形态的数据很少。这些SOS可能同时表现出亲核和亲电反应性，我们将其归因于S（II）和S（IV）互变异构体之间的相互转化。我们发现SOS可以通过亲核和亲电捕集剂衍生化而被原位捕集，然后以高分辨率LC MS为特征。在本报告中，我们比较了各种生物学上相关的氧化剂从H2S氧化形成SOS的过程。这些SOS在水溶液中的寿命相对较长，因此可能与所观察到的H2S的生理效应有关。

BACKGROUND & AIMS: :The here-reported identification of the LexA-binding sequence of Bdellovibrio bacteriovorus, a bacterial predator belonging to the delta-Proteobacteria, has made possible a detailed study of its LexA regulatory network. Surprisingly, only the lexA gene and a multiple gene cassette including dinP and dnaE homologues are regulated by the LexA protein in this bacterium. In vivo expression analyses have confirmed that this gene cassette indeed forms a polycistronic unit that, like the lexA gene, is DNA damage inducible in B. bacteriovorus. Conversely, genes such as recA, uvrA, ruvCAB, and ssb, which constitute the canonical core of the Proteobacteria SOS system, are not repressed by the LexA protein in this organism, hinting at a persistent selective pressure to maintain both the lexA gene and its regulation on the reported multiple gene cassette. In turn, in vitro experiments show that the B. bacteriovorus LexA-binding sequence is not recognized by other delta-Proteobacteria LexA proteins but binds to the cyanobacterial LexA repressor. This places B. bacteriovorus LexA at the base of the delta-Proteobacteria LexA family, revealing a high degree of conservation in the LexA regulatory sequence prior to the diversification and specialization seen in deeper groups of the Proteobacteria phylum.

背景与目标： ：这里报道的细菌deldel-Proteobacteria细菌捕食者Bdellovibrio细菌的LexA结合序列的鉴定，使得对其LexA调控网络的详细研究成为可能。令人惊讶的是，在该细菌中，只有lexA基因和包括dinP和dnaE同源物的多基因盒受该细菌中的LexA蛋白调控。体内表达分析已证实，该基因盒确实形成了一个多顺反子单元，就像lexA基因一样，在细菌噬菌芽孢杆菌中可诱导DNA损伤。相反，构成Proteobacteria SOS系统规范核心的诸如recA，uvrA，ruvCAB和ssb之类的基因在该生物体中并未受到LexA蛋白的抑制，这暗示着维持lexA基因及其基因的持续选择性压力报道的多基因盒的基因调控。反过来，体外实验表明，细菌噬菌芽孢杆菌LexA的结合序列不能被其他δ-ProteobacteriaLexA蛋白识别，但与蓝细菌LexA阻遏物结合。这将细菌噬菌芽孢杆菌LexA置于变形杆菌LexA家族的基础上，从而揭示了在更深层次的门氏杆菌中发现的多样化和专业化之前，LexA调控序列的高度保守性。

BACKGROUND & AIMS: Site-directed mutations in the Escherichia coli ssb gene were tested for the ability to complement a chromosomal ssb deletion for viability, and only the ssb W54-->G mutation failed to do so at the pSC101 copy level. Non-aromatic amino acid substitutions for SSB Trp-54 (ssb W54-->L and ssb W54-->S) produced the greatest effects on in vivo protein function including altered marker linkage subsequent to generalized transduction, extreme UV sensitivity, and a lack of ability to support SOS induction. Additionally, the ssb-113 (ssb P176-->S) mutation demonstrated the existence of both uvrA-dependent and uvrA-independent components of SOS induction. Although nucleotide excision repair appeared unaffected by alterations in the SSB protein, the mutational analysis suggests a direct role for SSB in recombinational repair.

背景与目标： 测试了大肠杆菌ssb基因中的定点突变与染色体ssb缺失互补的能力，而只有ssb W54-> G突变在pSC101复制水平上没有这样做。 SSB Trp-54的非芳香族氨基酸取代（ssb W54-> L和ssb W54-> S）对体内蛋白质功能产生最大影响，包括广义转导后标记连锁的改变，极高的紫外线敏感性和缺乏支持SOS归纳的能力。此外，ssb-113（ssb P176-> S）突变证明了SOS诱导的uvrA依赖性和uvrA依赖性组件均存在。尽管核苷酸切除修复似乎不受SSB蛋白改变的影响，但突变分析表明SSB在重组修复中具有直接作用。

BACKGROUND & AIMS: :Proteolysis is used by all forms of life for shaping the proteome in response to adverse environmental conditions in order to ensure optimal survival. Here we will address the role of proteolysis in helping cells respond to environmental stress, with a focus on the impact of proteolysis under DNA-damaging conditions and in maintenance of cellular homeostasis in response to metal exposure in bacteria.

背景与目标： ：蛋白水解被各种形式的生命用于应对不利的环境条件，从而形成蛋白质组，以确保最佳的存活率。在这里，我们将探讨蛋白水解在帮助细胞应对环境压力方面的作用，重点是在DNA破坏条件下蛋白水解的影响以及响应细菌中金属暴露而维持细胞稳态的作用。

BACKGROUND & AIMS: Several environmental organochlorines, some of which exhibit estrogenic activity, have been detected in human breast tissue and have been suggested as having a role in tumorigenesis. In this communication, we report the effects of DDT on c-erbB2 and c-met growth factor receptor tyrosine kinase and STATS signal transduction processes in human breast epithelial MCF-10A cells. p,p'-DDT at physiologically relevant concentrations (i.e. 10 nM) elevated c-erbB2, c-met and STAT1 alpha (p84/91) tyrosine phosphorylation, stimulated Grb2-Sos1 association and elevated MAPK phosphorylation. In contrast, o,p'-DDT under identical conditions failed to stimulate either c-erbB2 or c-met tyrosine phosphorylation, demonstrating a structural specificity for this effect. p,p'-DDT also stimulated breast epithelial cell proliferation, as evidenced by 3H thymidine incorporation and analysis of cell doubling times. These results provide evidence of additional pathways by which environmental chemicals may stimulate cell proliferation and/or tumorigenesis and thereby function as xenomitogens.

背景与目标： 在人的乳腺组织中已经检测到几种环境有机氯，其中一些具有雌激素活性，并被认为在肿瘤发生中起作用。在此交流中，我们报告了滴滴涕对人乳腺上皮MCF-10A细胞中c-erbB2和c-met生长因子受体酪氨酸激酶和STATS信号转导过程的影响。生理相关浓度（即10 nM）的p，p'-DDT升高的c-erbB2，c-met和STAT1α（p84 / 91）酪氨酸磷酸化，刺激的Grb2-Sos1缔合和MAPK磷酸化升高。相反，在相同条件下的o，p'-DDT不能刺激c-erbB2或c-met酪氨酸磷酸化，证明了这种作用的结构特异性。 p，p'-DDT也刺激了乳腺上皮细胞的增殖，如3H胸腺嘧啶核苷的掺入和细胞倍增时间的分析所证明。这些结果提供了其他途径的证据，环境化学物质可通过这些途径刺激细胞增殖和/或肿瘤发生，从而充当异种有丝分裂原。