Publications by authors named "Haijuan Yang"

14 Publications

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Mechanism of strand exchange from RecA-DNA synaptic and D-loop structures.

Nature 2020 10 14;586(7831):801-806. Epub 2020 Oct 14.

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

The strand-exchange reaction is central to homologous recombination. It is catalysed by the RecA family of ATPases, which form a helical filament with single-stranded DNA (ssDNA) and ATP. This filament binds to a donor double-stranded DNA (dsDNA) to form synaptic filaments, which search for homology and then catalyse the exchange of the complementary strand, forming either a new heteroduplex or-if homology is limited-a D-loop. How synaptic filaments form, search for homology and catalyse strand exchange is poorly understood. Here we report the cryo-electron microscopy analysis of synaptic mini-filaments with both non-complementary and partially complementary dsDNA, and structures of RecA-D-loop complexes containing a 10- or a 12-base-pair heteroduplex. The C-terminal domain of RecA binds to dsDNA and directs it to the RecA L2 loop, which inserts into and opens up the duplex. The opening propagates through RecA sequestering the homologous strand at a secondary DNA-binding site, which frees the complementary strand to sample pairing with the ssDNA. At each RecA step, there is a roughly 20% probability that duplex opening will terminate and the as-yet-unopened dsDNA portion will bind to another C-terminal domain. Homology suppresses this process, through the cooperation of heteroduplex pairing with the binding of ssDNA to the secondary site, to extend dsDNA opening. This mechanism locally limits the length of ssDNA sampled for pairing if homology is not encountered, and could allow for the formation of multiple, widely separated synapses on the donor dsDNA, which would increase the likelihood of encountering homology. These findings provide key mechanistic insights into homologous recombination.
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http://dx.doi.org/10.1038/s41586-020-2820-9DOI Listing
October 2020

Preparation and Properties of Self-Healing and Self-Lubricating Epoxy Coatings with Polyurethane Microcapsules Containing Bifunctional Linseed Oil.

Polymers (Basel) 2019 Sep 27;11(10). Epub 2019 Sep 27.

School of Resources, Environment and Materials, Guangxi University, Nanning 530004, China.

An organic coating is commonly used to protect metal from corrosion, but it is prone to failure due to microcracks generated by internal stress and external mechanical action. The self-healing and self-lubricating achieved in the coating is novel, which allows an extension of life by providing resistance to damage and repair after damage. In this study, a new approach to microencapsulating bifunctional linseed oil with polyurethane shell by interfacial polymerization. Moreover, the self-healing and self-lubricating coatings with different concentrations of microcapsules were developed. The well-dispersed microcapsules showed a regular spherical morphology with an average diameter of ~64.9 μm and a core content of 74.0 wt.%. The results of the salt spray test demonstrated that coatings containing microcapsules still possess anticorrosion, which is improved with the increase of microcapsules content, after being scratched. The results of electrochemical impedance spectroscopy showed a |Z| value of 10 Ω·cm for pure epoxy coating after being immersed for 3 days, whereas the coating with 20 wt.% microcapsules was the highest, 10 Ω·cm. The results of friction wear showed that the tribological performance of the coating was enhanced greatly as microcapsule concentration reached 10 wt.% or more, which showed a 86.8% or more reduction in the friction coefficient compared to the pure epoxy coating. These results indicated that the coatings containing microcapsules exhibited excellent self-healing and self-lubricating properties, which are positively correlated with microcapsules content.
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http://dx.doi.org/10.3390/polym11101578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836264PMC
September 2019

The Influence of Land Use Change on Ecosystem Service Value in Shangzhou District.

Int J Environ Res Public Health 2019 04 12;16(8). Epub 2019 Apr 12.

College of Urban and Environmental Science, Northwest University, Xi'an 710127, China.

Land use change has an impact on the ecosystem service value because it changes the structure and function of ecosystems. This paper analyzed the changes in land use during the period from 2000 to 2015 in Shangzhou district, and used the equivalent value of ecological services per unit area of land ecosystem combining the natural and economic conditions of Shangzhou district. Based on this method, the ecological service value of Shangzhou district was estimated, and the impact of land use change on the ecological service value was analyzed. The results showed that: (1) the main types of land use in Shangzhou district were grassland, woodland and farmland, among which the contribution rate of woodland to the value of local ecosystem services was the highest; (2) the overall trend in the ecosystem service value in Shangzhou district increased between 2000 and 2015, from 10.74 × 10 yuan in 2000 to 20.32 × 10 yuan in 2015, which is the result of the combined effects of regional economic development and changes in the natural environment and land use patterns; and (3) the main reason for the value increase of ecosystem services in Shangzhou district between 2000 and 2015 was that the grain-for-green policy transformed a considerable amount of farmland into woodland, while the main reasons for a decline in value was the expansion of built-up land that occupied other types of land.
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http://dx.doi.org/10.3390/ijerph16081321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518006PMC
April 2019

Voting Simulation based Agglomerative Hierarchical Method for Network Community Detection.

Sci Rep 2018 05 23;8(1):8064. Epub 2018 May 23.

Lanzhou University, School of Information Science and Engineering, Lanzhou, 730000, China.

Community detection has been paid much attention in many fields in recent years, and a great deal of community-detection methods have been proposed. But the time consumption of some of them is heavy, limiting them from being applied to large-scale networks. On the contrary, there exist some lower-time-complexity methods. But most of them are non-deterministic, meaning that running the same method many times may yield different results from the same network, which reduces their practical utility greatly in real-world applications. To solve these problems, we propose a community-detection method in this paper, which takes both the quality of the results and the efficiency of the detecting procedure into account. Moreover, it is a deterministic method which can extract definite community structures from networks. The proposed method is inspired by the voting behaviours in election activities in the social society, in which we first simulate the voting procedure on the network. Every vertex votes for the nominated candidates following the proposed voting principles, densely connected groups of vertices can quickly reach a consensus on their candidates. At the end of this procedure, candidates and their own voters form a group of clusters. Then, we take the clusters as initial communities, and agglomerate some of them into larger ones with high efficiency to obtain the resulting community structures. We conducted extensive experiments on some artificial networks and real-world networks, the experimental results show that our proposed method can efficiently extract high-quality community structures from networks, and outperform the comparison algorithms significantly.
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http://dx.doi.org/10.1038/s41598-018-26415-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966462PMC
May 2018

Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.

Nature 2017 12 13;552(7685):368-373. Epub 2017 Dec 13.

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.
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http://dx.doi.org/10.1038/nature25023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750076PMC
December 2017

Role of basophils in rheumatoid arthritis (Review).

Exp Ther Med 2015 May 24;9(5):1567-1571. Epub 2015 Feb 24.

Institute of Nephrology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.

The T helper (Th)1/Th2 imbalance plays a crucial role in the development of rheumatoid arthritis (RA). It is well known that basophils can affect the Th1/Th2 balance by enhancing the Th2 response, while impairing the Th1 response, which is known to be involved in the development of a number of diseases. However, limited information is available with regard to the role of basophils in RA. Decreased levels of circulating basophils and a dominant Th1 response have been reported in adult patients with RA, while children with juvenile RA have been largely found to have increased levels of circulating basophils and a dominant Th2 response. Furthermore, the circulating basophils in the two conditions have an activated phenotype and are associated with disease activity. In addition, a longitudinal study found the Th2 response was dominant in the early stages of RA, while the Th1 response was dominant in long-term chronic RA. These observations indicate that basophils may be involved in the development of RA by affecting the Th1/Th2 balance, particularly in the early stages of RA. Therefore, targeting basophils may be a novel therapeutic strategy for the treatment of RA; however, further investigation is required.
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http://dx.doi.org/10.3892/etm.2015.2312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471658PMC
May 2015

Optical microscopy with flexible axial capabilities using a vari-focus liquid lens.

J Microsc 2015 Jun 25;258(3):212-22. Epub 2015 Mar 25.

Key Laboratory of Precision Opto-Mechatronics Technology of Education Ministry, Beijing, China.

The axial imaging range of optical microscopy is restricted by its fixed working plane and limited depth of field. In this paper, the axial capabilities of an off-the-shelf microscope is improved by inserting a liquid lens, which can be controlled by a driving electrical voltage, into the optical path of the microscope. First, the numerical formulas of the working distance and the magnification with the variation of the focus of the liquid lens are inferred using a ray tracing method and conclusion is obtained that the best position for inserting a liquid lens with consistent magnification is the aperture plane and the rear focal plane of the objective lens. Second, with the liquid lens embedded in the microscope, the numerical relationship between the magnification and the working distance of the proposed flexible-axial-capability microscope and the liquid lens driving voltage is calibrated and fitted using the inferred numerical formulas. Third, techniques including autofocus, extending depth of field and three-dimensional imaging are researched and applied, improving the designed microscope to not only flexibly control its working distance, but also to extend the depth of field near the variable working plane. Experiments show that the presented flexible-axial-capability microscope has a long working distance range of 8 mm, and by calibrating the magnification curve within the working distance range, samples can be observed and measured precisely. The depth of field can be extended to 400 μm from the variable working plane and is 20 times that of the off-the-shelf microscope.
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http://dx.doi.org/10.1111/jmi.12235DOI Listing
June 2015

mTOR kinase structure, mechanism and regulation.

Nature 2013 May 1;497(7448):217-23. Epub 2013 May 1.

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.
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http://dx.doi.org/10.1038/nature12122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512754PMC
May 2013

Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structures.

Nature 2008 May;453(7194):489-4

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

The RecA family of ATPases mediates homologous recombination, a reaction essential for maintaining genomic integrity and for generating genetic diversity. RecA, ATP and single-stranded DNA (ssDNA) form a helical filament that binds to double-stranded DNA (dsDNA), searches for homology, and then catalyses the exchange of the complementary strand, producing a new heteroduplex. Here we have solved the crystal structures of the Escherichia coli RecA-ssDNA and RecA-heteroduplex filaments. They show that ssDNA and ATP bind to RecA-RecA interfaces cooperatively, explaining the ATP dependency of DNA binding. The ATP gamma-phosphate is sensed across the RecA-RecA interface by two lysine residues that also stimulate ATP hydrolysis, providing a mechanism for DNA release. The DNA is underwound and stretched globally, but locally it adopts a B-DNA-like conformation that restricts the homology search to Watson-Crick-type base pairing. The complementary strand interacts primarily through base pairing, making heteroduplex formation strictly dependent on complementarity. The underwound, stretched filament conformation probably evolved to destabilize the donor duplex, freeing the complementary strand for homology sampling.
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http://dx.doi.org/10.1038/nature06971DOI Listing
May 2008

Tel2 regulates the stability of PI3K-related protein kinases.

Cell 2007 Dec;131(7):1248-59

Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

We report an unexpected role for Tel2 in the expression of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Although Tel2 was identified as a budding yeast gene required for the telomere length maintenance, we found no obvious telomeric function for mammalian Tel2. Targeted gene deletion showed that mouse Tel2 is essential in embryonic development, embryonic stem (ES) cells, and embryonic fibroblasts. Conditional deletion of Tel2 from embryonic fibroblasts compromised their response to IR and UV, diminishing the activation of checkpoint kinases and their downstream effectors. The effects of Tel2 deletion correlated with significantly reduced protein levels for the PI3K-related kinases ataxia telangiectasia mutated (ATM), ATM and Rad3 related (ATR), DNA-dependent protein kinase catalytic subunit ataxia (DNA-PKcs). Tel2 deletion also elicited specific depletion of the mammalian target of rapamycin (mTOR), suppressor with morphological effect on genitalia 1 (SMG1), and transformation/transcription domain-associated protein (TRRAP), and curbed mTOR signaling, indicating that Tel2 affects all six mammalian PIKKs. While Tel2 deletion did not alter PIKK mRNA levels, in vivo pulse labeling experiments showed that Tel2 controls the stability of ATM and mTOR. Each of the PIKK family members associated with Tel2 in vivo and in vitro experiments indicated that Tel2 binds to part of the HEAT repeat segments of ATM and mTOR. These data identify Tel2 as a highly conserved regulator of PIKK stability.
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http://dx.doi.org/10.1016/j.cell.2007.10.052DOI Listing
December 2007

Ubiquitination regulates PTEN nuclear import and tumor suppression.

Cell 2007 Jan;128(1):141-56

Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of PTEN.
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http://dx.doi.org/10.1016/j.cell.2006.11.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855245PMC
January 2007

The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction.

Nature 2005 Feb;433(7026):653-7

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

The BRCA2 tumour suppressor is essential for the error-free repair of double-strand breaks (DSBs) in DNA by homologous recombination. This is mediated by RAD51, which forms a nucleoprotein filament with the 3' overhanging single-stranded DNA (ssDNA) of the resected DSB, searches for a homologous donor sequence, and catalyses strand exchange with the donor DNA. The 3,418-amino-acid BRCA2 contains eight approximately 30-amino-acid BRC repeats that bind RAD51 (refs 5, 6) and a approximately 700-amino-acid DBD domain that binds ssDNA. The isolated BRC and DBD domains have the opposing effects of inhibiting and stimulating recombination, respectively, and the role of BRCA2 in repair has been unclear. Here we show that a full-length BRCA2 homologue (Brh2) stimulates Rad51-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA (dsDNA) and ssDNA, with strict specificity for the 3' overhang polarity of a resected DSB. These results establish a BRCA2 function in RAD51-mediated DSB repair and explain the loss of this repair capacity in BRCA2-associated cancers.
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http://dx.doi.org/10.1038/nature03234DOI Listing
February 2005

The BRCA2-interacting protein DSS1 is vital for DNA repair, recombination, and genome stability in Ustilago maydis.

Mol Cell 2003 Oct;12(4):1043-9

Department of Microbiology and Immunology, Hearst Microbiology Research Center, Weill Medical College of Cornell University, New York, NY 10021, USA.

DSS1 encodes a small acidic protein shown in recent structural studies to interact with the DNA binding domain of BRCA2. Here we report that an ortholog of DSS1 is present in Ustilago maydis and associates with Brh2, the BRCA2-related protein, thus recapitulating the protein partnership in this genetically amenable fungus. Mutants of U. maydis deleted of DSS1 are extremely radiation sensitive, deficient in recombination, defective in meiosis, and disturbed in genome stability; these phenotypes mirror previous observations of U. maydis mutants deficient in Brh2 or Rad51. These findings conclusively show that Dss1 constitutes a protein with a significant role in the recombinational repair pathway in U. maydis, and imply that it plays a similar key role in the recombination systems of organisms in which recombinational repair is BRCA2 dependent.
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http://dx.doi.org/10.1016/s1097-2765(03)00367-8DOI Listing
October 2003

BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.

Science 2002 Sep;297(5588):1837-48

Department of Pharmacology, Sloan-Kettering Division, Joan and Sanford I. Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.

Mutations in the BRCA2 (breast cancer susceptibility gene 2) tumor suppressor lead to chromosomal instability due to defects in the repair of double-strand DNA breaks (DSBs) by homologous recombination, but BRCA2's role in this process has been unclear. Here, we present the 3.1 angstrom crystal structure of a approximately 90-kilodalton BRCA2 domain bound to DSS1, which reveals three oligonucleotide-binding (OB) folds and a helix-turn-helix (HTH) motif. We also (i) demonstrate that this BRCA2 domain binds single-stranded DNA, (ii) present its 3.5 angstrom structure bound to oligo(dT)9, (iii) provide data that implicate the HTH motif in dsDNA binding, and (iv) show that BRCA2 stimulates RAD51-mediated recombination in vitro. These findings establish that BRCA2 functions directly in homologous recombination and provide a structural and biochemical basis for understanding the loss of recombination-mediated DSB repair in BRCA2-associated cancers.
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http://dx.doi.org/10.1126/science.297.5588.1837DOI Listing
September 2002