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聚合酶链反应 polymerase chain reaction（PCR） 抗核抗体 anti-nuclear antibody（ANA） 抗神经节苷脂抗体 anti-ganglioside antibody（AGA） 抗双链DNA抗体 anti-double stranded DNA antibody（dsDNA） 抗心磷脂抗体 anti-cardiolipin antibody（ACA） 抗中性粒细胞胞质抗体 anti—neutrophilcytoplasmicantibody（ANCA）可提取性核抗原extractablenuclearantigen（ENA）

Exosomes, small membrane vesicles （30-100 nm） of endocytic origin secreted by most cell types, contain functional biomolecules, which can be horizontally transferred to recipient cells [1]. Exosomes bear a specific protein and lipid composition, and carry a select set of functional mRNAs and microRNAs [2]. Recently, our group has shown that c-Met shed in exosomes can promote a proangiogenic and prometastatic phenotype in bone marrow-derived progenitor cells during melanoma progression [3]. In previous research, retrotransposon RNA transcripts, single-stranded DNA （ssDNA）,

Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism re- mains unclear. This study considers the widely applied cytotoxic agent irinotecan （CPT-11） as a representative agent and demonstrates that treatment induces massive release of double-strand DNA from the intestine that accounts for the dose-limiting intestinal toxicity of the compound. Specifically, ＂self-DNA＂ released through exosome secretion en- ters the cytosol of innate immune cells and activates the AIM2 （absent in melanoma 2） inflammasome. This leads to mature IL-Iβ and IL-18 secretion and induces intestinal mucositis and late-onset diarrhoea. Interestingly, abrogation of AIM2 signalling, either in AIM2-deficient mice or by a pharmacological inhibitor such as thalidomide, significantly reduces the incidence of drug-induced diarrhoea without affecting the anticancer efficacy of CPT-11. These findings provide mechanistic insights into how chemotherapy triggers innate immune responses causing intestinal toxicity, and reveal new chemotherapy regimens that maintain anti-tumour effects but circumvent the associated adverse in- flammatory response.

The identification of hydroxylmethyl- and formylpyrimidines in genomic DNA was a landmark event in epigenetics. Numerous laboratories in related fields are investigating the biology of these and other nucleic acid modifications. However, limitations in the ability to detect and synthesize appropriate modifications are an impediment. Herein, we explored a remarkable development in the selective detection of 5-formyluracil in both single-stranded and double-stranded DNA under mild conditions. The ＂switch-on＂ specificity towards 5-formyluracil enabled a high signal-to-noise ratio in qualitatively and quantitatively detecting materials containing 5-formyluradl, which is not affected by the presence of abasic sites and 5-formylcytosine, the modified cytosine counterpart of 5-formyluracil. In summar~ the innoxiousness, convenience, and cost-effidency of the 5-formyluracil phosphoramidite synthetic routine would promote the understanding of the epi~enetic role of this natural thvmidine modification.

Chemotherapy is a predominant strategy to treat cancer and is of- ten associated with toxicities like severe diarrhea that puts patients at additional risk and can hinder treatment strategies. Lian et aL recently explored the immune-mediated mechanisms of Irinotecan-induced di- arrhea in colorectal cancer and found that double-stranded DNA in small vesicles can launch inflammation pathways in immune cells through the cytosolic DNA sensor AIM2.

Sighting and binding of double-stranded DNA （ds- DNA） by a sensor in the cytoplasm trigger the activation of the immune-surveillance pathways [1]. The crystal structure of absent in melanoma 2 （AIM2） bound with DNA conclusively defines the role of AIM2 as a sensor in the innate immune system [2]. AIM2 belongs to the PYHIN family of proteins and contains a pyrin domain （PYD） followed by a hematopoietic interferon-inducible nuclear protein （HIN） domain （Figure 1A）. AIM2 binds DNA via the HIN domain and recruits the adaptor pro- tein apoptosis-associated speck-like protein containing a caspase recruitment domain （ASC） via the PYD. ASC in turn recruits caspase-1 via CARD-CARD interaction, resulting in the formation of inflammasomes comprised of AIM2, ASC and caspase-1. The molecular crowding of the AIM2 inflammasome ensures the proteolysis and transactivation of caspase-1. Activated caspase-1 cleaves pro-IL-1 ]3 and pro-IL-18 into their mature proinflamma- tory forms [3, 4]. The termination of inflammatory responses originated from inflammasomes can be accomplished by employing naturally occurring dominant-negative antagonists [4]. Dominant-negative proteins are similar to their canoni- cal counterparts except for a missing effector domain, so that they cannot relay the signals any further. They out- compete their canonical counterparts for ligands or bind- ing sites and thus block the downstream signal transduc- tion. Such regulation is essential for maintaining cellular homeostasis. To regulate inflammasome activation, mice have evolved a strategy that has so far not been discov- ered in humans. Mice use the H1N-only protein, p202, to sequester cytoplasmic dsDNA and render it unavailable for its canonical sensor, AIM2 [4]. p202 contains two HIN domains （HINa and H1Nb）, but lacks the PYD （Fig- ure 1A）. Therefore, p202 is unable to recruit the adaptor ASC, and its binding to DNA results in the termination of inflammasome signaling. The significance of p202 in the regulation of the innate immune responses is exem- plified by the fact that dysregulation of p202 function hasbeen linked to increased susceptibility to systemic lupus erythematosus [5]. To more clearly understand the mechanism of inhibi- tion of AIM2-mediated signaling by p202, it is essential to solve the structure of p202 in complex with DNA and compare it with that of AIM2 complexed with DNA. p202 has so far only been detected in mice. To compare the structure of AIM2 and p202 from the same species, we first solved the structure of the H1N domain of mu- rine AIM2 （mAIM2） in complex with dsDNA to 2.23 A resolution （Supplementary information, Table S1）. Although a 12-base pair （bp） long dsDNA was used for the crystallization, the HIN domain of mAIM2 seems to have lined up the DNA oligonucleotides end to end, gen- erating an appearance of a long and contiguous stretch of B-form DNA with putative major and minor grooves. As expected, the overall structure of the H1N domain of mAIM2 （Figure 1B） closely mirrors the structure of its human counterpart [2] （Supplementary information, Fig- ure S 1）. Minor deviations are observed at the N-terminus and in the loop regions. The surface electrostatic poten- tial distribution is similar, implying that the mechanism of tethering dsDNA is similar between human and mouse AIM2. The HIN domain of AIM2 consists of two oligonucle- otide/oligosaccharide （OB） folds [6] linked via a flexible linker （Figure 1B）. The proximal and distal OB folds are referred to as OB1 and OB2, respectively. Similar to the human ortholog, mAIM2 uses the helix-loop-helix motif located in the linker to engage DNA （Figure 1C）. Specifically, a short helix containing two turns is inserted horizontally to the vertical axis of the DNA spiral （Figure 1C）. Amino acids from the loop connecting helices ul and a2, and from helix ct2 interact with the major groove （Figure 1C）. A couple of interactions between OB2 and the DNA backbone are also observed. Residues N244, N245, K248, R249, R251, R255, K258, 0262 K273,

Histone-fold proteins typically assemble in multiprotein complexes to bind duplex DNA. However, one histone-fold complex, MHF, associates with Fanconi anemia （FA） protein FANCM to form a branched DNA remodeling complex that senses and repairs stalled replication forks and activates FA DNA damage response network. How the FANCM- MHF complex recognizes branched DNA is unclear. Here, we solved the crystal structure of MHF and its complex with the MHF-interaction domain （referred to as MID） of FANCM, and performed structure-guided mutagenesis. We found that the MID-MHF complex consists of one histone H3-H4-1ike MHF heterotetramer wrapped by a single polypeptide of MID. We identified a zinc atom-liganding structure at the central interface between MID and MHF that is critical for stabilization of the complex. Notably, the DNA-binding surface of MHF was altered by MID in both electrostatic charges and allosteric conformation. This leads to a switch in the DNA-binding preference -- from duplex DNA by MHF alone, to branched DNA by the MID-MHF complex. Mutations that disrupt either the com- posite DNA-binding surface or the protein-protein interface of the MID-MHF complex impaired activation of the FA network and genome stability. Our data provide the structural basis of how FANCM and MHF work together to recognize branched DNA, and suggest a novel mechanism by which histone-fold complexes can be remodeled by their partners to bind special DNA structures generated during DNA metabolism.

Two recent papers in Science il lustrate how the prokaryotic CRIS PRCas immune system machinery, which typically targets invasive genetic elements such as viruses and plasmids, can be converted into a sophisticated molecular tool for nextgeneration human genome edit ing. The versatile Cas9 RNAguided endonuclease can be readily repro grammed using customizable small RNAs for sequencespecific single or doublestranded DNA cleavage. Molecular biologists can now order restriction enzymes h la carte, to target any DNA template and generate cleav age at any chosen site precisely, without the agony of finding the right cutter, or the caveat to settle for the nearest ac ceptable site. Even better, the chef also offers the choice of doublestranded DNA blunt cleavage, or strandspecific nicking. Indeed, two recent milestone reports in Science [1, 2] describe the diversion of the CRISPRCas bacte rial adaptive immune system in novel genome editing applications in mam malian cells. In bacteria and archaea, CRISPR （clustered regularly interspaced short palindromic repeats） and CRISPRasso ciated proteins （Cas） naturally provide adaptive immunity against viruses and plasmids through the uptake and stock piling of small fragments （sequences of about 30 bp named ＂spacers＂） of the encountered genetic elements into CRISPR arrays, in between direct re peats [3]. The subsequent transcription ofa CRISPR array into a precursor RNA （precrRNA）, followed by a maturation step in which the precrRNA is diced into smaller CRISPR RNAs （crRNAs）,produces a cocktail of small interfering RNAs that are loaded onto the patrolling Casencoded machinery involving helicase and nuclease activities to specifically target and destroy nucleic acid showing sequence complementar ity to the spacers [4]. Although generic, this scheme shows marked idiosyncra sies when considering the numerous and highly diverse CRISPRCas sys tems that have been examined [5]. For instance, the thoroughly studied Type II systems require an additional, small noncoding RNA called transactivating CRISPR RNA （tracrRNA） to achieve the precrRNA maturation step （Figure 1A） [6]. To date, CRISPRCas systems have been used to enhance resistance against viruses in bacteria of industrial interest, and studies have shown that bacteria can be vaccinated to preclude the uptake （and dissemination） of anti biotic resistance genes [7]. The hyper variable nature of these rapidly evolving loci has also been used for phylogenetic and evolutionary studies. Until recently, the most advanced genome editing technologies involved three families of sitespecific nucle ases, namely zinc finger nucleases （ZFNs）, transcription activatorlike effector nucleases （TALENs）, and the engineered homing meganucleases [8]. These technologies can trigger error prone sequence repair at the cleavage site through either nonhomologous end joining （NHEJ） or homology directed repair （HDR） pathways, gen erating genetically ＂edited＂ variants. However, despite successful uses in various eukaryotic hosts and model systems, they all present important limitations that still warrant furtherdevelopments in this field. Notably, offtarget mutagenesis activity due to imperfect specificity in target sequence recognition may explain certain cases of nuclease toxicity within transfected cells, but above all is the significant time and cost requirement for （re）developing such engineered, customized proteins for each desired target sequence. A stepchange in genome editing perspectives occurred in 2012 when Jinek et al. [9] reported that the strep tococcal Cas9 endonuclease can drive sequencespecific DNA cleavage in the presence of a synthetic, hybrid RNA molecule mimicking both crRNA and tracrRNA. Sitedirected mutagenesis of Cas9 in either the RuvC or HNHmotif showed strand cleavage specificity, thereby providing two strandspecific nickases, in addition to the wildtype endonuclease [9, 10].

G-quadruplexes comprise a class of secondary structures that are formed in guanine-rich sequences in eukaryotic genomes and play a crucial role in the regulation of many biological events. G-quadruplexes have become targets for anticancer drugs with high selectivity vs. duplex DNA and low cytotoxicity against normal cells. Natural products and their derivatives display pol- ymorphism, structural complexity, and potent activity. It is, therefore, reasonable to seek ligands targeting G-quadruplexes from natural products. Recently, many successful examples have been reported, showing ligands with excellent anticancer ac- tivities. In this review, we summarized the development of research on natural products and derivatives that target G-quadruplex structures in an effort to guide future studies.

Deoxyribonucleic acid（DNA） carries the genetic information in all living organisms. It consists of two interwound single-stranded（ss） strands, forming a double-stranded（ds） DNA with a right-handed double-helical conformation. The two strands are held together by highly specific basepairing interactions and are further stabilized by stacking between adjacent basepairs. A transition from a dsDNA to two separated ssDNA is called melting and the reverse transition is called hybridization. Applying a tensile force to a dsDNA can result in a particular type of DNA melting, during which one ssDNA strand is peeled away from the other. In this work, we studied the kinetics of strand-peeling and hybridization of short DNA under tensile forces. Our results show that the force-dependent strand-peeling and hybridization can be described with a simple two-state model. Importantly, detailed analysis of the force-dependent transition rates revealed that the transition state consists of several basepairs dsDNA.