The Experts below are selected from a list of 1188 Experts worldwide ranked by ideXlab platform

Jielin Liu - One of the best experts on this subject based on the ideXlab platform.

  • screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting blm Helicase
    BMC Cancer, 2019
    Co-Authors: Wangming Zhang, Shuang Yang, Jinhe Liu, Linchun Bao, Weidong Pan, Yanchao Jiao, Jielin Liu
    Abstract:

    The high expression of BLM (Bloom Syndrome) Helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to screen potential antiproliferative small molecules from 12 small molecules (the derivatives of bisbenzylisoquinoline alkaloids tetrandrine and fangchinoline) by targeting BLM642–1290 Helicase. Then we explore the inhibitory mechanism of those small molecules on proliferation of MDA-MB-435 breast cancer cells. Fluorescence polarization technique was used to screen small molecules which inhibited the DNA binding and unwinding of BLM642–1290 Helicase. The effects of positive small molecules on the ATPase and conformation of BLM642–1290 Helicase were studied by the malachite green-phosphate ammonium molybdate colorimetry and ultraviolet spectral scanning, respectively. The effects of positive small molecules on growth of MDA-MB-435 cells were studied by MTT method, colony formation and cell counting method. The mRNA and protein levels of BLM Helicase in the MDA-MB-435 cells after positive small molecule treatments were examined by RT-PCR and ELISA, respectively. The compound HJNO (a tetrandrine derivative) was screened out which inhibited the DNA binding, unwinding and ATPase of BLM642–1290 Helicase. That HJNO could bind BLM642–1290Helicase to change its conformationcontribute to inhibiting the DNA binding, ATPase and DNA unwinding of BLM642–1290 Helicase. In addition, HJNO showed its inhibiting the growth of MDA-MB-435 cells. The values of IC50 after drug treatments for 24 h, 48 h and 72 h were 19.9 μmol/L, 4.1 μmol/L and 10.9 μmol/L, respectively. The mRNA and protein levels of BLM Helicase in MDA-MB-435 cells increased after HJNO treatment. Those showed a significant difference (P < 0.05) compared with negative control when the concentrations of HJNO were 5 μmol/L and 10 μmol/L, which might contribute to HJNO inhibiting the DNA binding, ATPase and DNA unwinding of BLM Helicase. The small molecule HJNO was screened out by targeting BLM642–1290 Helicase. And it showed an inhibition on MDA-MB-435 breast cancer cells expansion.

Kristina H Schmidt - One of the best experts on this subject based on the ideXlab platform.

  • a novel cell cycle regulated interaction of the Bloom Syndrome Helicase blm with mcm6 controls replication linked processes
    Nucleic Acids Research, 2021
    Co-Authors: Vivek M Shastri, Veena Subramanian, Kristina H Schmidt
    Abstract:

    The Bloom Syndrome DNA Helicase BLM contributes to chromosome stability through its roles in double-strand break repair by homologous recombination and DNA replication fork restart during the replication stress response. Loss of BLM activity leads to Bloom Syndrome, which is characterized by extraordinary cancer risk and small stature. Here, we have analyzed the composition of the BLM complex during unperturbed S-phase and identified a direct physical interaction with the Mcm6 subunit of the minichromosome maintenance (MCM) complex. Using distinct binding sites, BLM interacts with the N-terminal domain of Mcm6 in G1 phase and switches to the C-terminal Cdt1-binding domain of Mcm6 in S-phase, with a third site playing a role for Mcm6 binding after DNA damage. Disruption of Mcm6-binding to BLM in S-phase leads to supra-normal DNA replication speed in unperturbed cells, and the Helicase activity of BLM is required for this increased replication speed. Upon disruption of BLM/Mcm6 interaction, repair of replication-dependent DNA double-strand breaks is delayed and cells become hypersensitive to DNA damage and replication stress. Our findings reveal that BLM not only plays a role in the response to DNA damage and replication stress, but that its physical interaction with Mcm6 is required in unperturbed cells, most notably in S-phase as a negative regulator of replication speed.

  • cellular defects caused by hypomorphic variants of the Bloom Syndrome Helicase gene blm
    Molecular Genetics & Genomic Medicine, 2016
    Co-Authors: Vivek M Shastri, Kristina H Schmidt
    Abstract:

    Background Bloom Syndrome is an autosomal recessive disorder characterized by extraordinary cancer incidence early in life and an average life expectancy of ~27 years. Premature stop codons in BLM, which encodes a DNA Helicase that functions in DNA double-strand-break repair, make up the vast majority of Bloom Syndrome mutations, with only 13 single amino acid changes identified in the Syndrome. Sequencing projects have identified nearly one hundred single nucleotide variants in BLM that cause amino acid changes of uncertain significance. Methods and Results Here, in addition to identifying five BLM variants incapable of complementing certain defects of Bloom Syndrome cells, making them candidates for new Bloom Syndrome causing mutations, we characterize a new class of BLM variants that cause some, but not all, cellular defects of Bloom Syndrome. We find elevated sister-chromatid exchanges, a delayed DNA damage response and inefficient DNA repair. Conversely, hydroxyurea sensitivity and quadriradial chromosome accumulation, both characteristic of Bloom Syndrome cells, are absent. These intermediate variants affect sites in BLM that function in ATP hydrolysis and in contacting double-stranded DNA. Conclusion Allele frequency and cellular defects suggest candidates for new Bloom Syndrome causing mutations, and intermediate BLM variants that are hypomorphic which, instead of causing Bloom Syndrome, may increase a person's risk for cancer or possibly other Bloom-Syndrome-associated disorders, such as type-2 diabetes.

Wangming Zhang - One of the best experts on this subject based on the ideXlab platform.

  • screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting blm Helicase
    BMC Cancer, 2019
    Co-Authors: Wangming Zhang, Shuang Yang, Jinhe Liu, Linchun Bao, Weidong Pan, Yanchao Jiao, Jielin Liu
    Abstract:

    The high expression of BLM (Bloom Syndrome) Helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to screen potential antiproliferative small molecules from 12 small molecules (the derivatives of bisbenzylisoquinoline alkaloids tetrandrine and fangchinoline) by targeting BLM642–1290 Helicase. Then we explore the inhibitory mechanism of those small molecules on proliferation of MDA-MB-435 breast cancer cells. Fluorescence polarization technique was used to screen small molecules which inhibited the DNA binding and unwinding of BLM642–1290 Helicase. The effects of positive small molecules on the ATPase and conformation of BLM642–1290 Helicase were studied by the malachite green-phosphate ammonium molybdate colorimetry and ultraviolet spectral scanning, respectively. The effects of positive small molecules on growth of MDA-MB-435 cells were studied by MTT method, colony formation and cell counting method. The mRNA and protein levels of BLM Helicase in the MDA-MB-435 cells after positive small molecule treatments were examined by RT-PCR and ELISA, respectively. The compound HJNO (a tetrandrine derivative) was screened out which inhibited the DNA binding, unwinding and ATPase of BLM642–1290 Helicase. That HJNO could bind BLM642–1290Helicase to change its conformationcontribute to inhibiting the DNA binding, ATPase and DNA unwinding of BLM642–1290 Helicase. In addition, HJNO showed its inhibiting the growth of MDA-MB-435 cells. The values of IC50 after drug treatments for 24 h, 48 h and 72 h were 19.9 μmol/L, 4.1 μmol/L and 10.9 μmol/L, respectively. The mRNA and protein levels of BLM Helicase in MDA-MB-435 cells increased after HJNO treatment. Those showed a significant difference (P < 0.05) compared with negative control when the concentrations of HJNO were 5 μmol/L and 10 μmol/L, which might contribute to HJNO inhibiting the DNA binding, ATPase and DNA unwinding of BLM Helicase. The small molecule HJNO was screened out by targeting BLM642–1290 Helicase. And it showed an inhibition on MDA-MB-435 breast cancer cells expansion.

Vivek M Shastri - One of the best experts on this subject based on the ideXlab platform.

  • a novel cell cycle regulated interaction of the Bloom Syndrome Helicase blm with mcm6 controls replication linked processes
    Nucleic Acids Research, 2021
    Co-Authors: Vivek M Shastri, Veena Subramanian, Kristina H Schmidt
    Abstract:

    The Bloom Syndrome DNA Helicase BLM contributes to chromosome stability through its roles in double-strand break repair by homologous recombination and DNA replication fork restart during the replication stress response. Loss of BLM activity leads to Bloom Syndrome, which is characterized by extraordinary cancer risk and small stature. Here, we have analyzed the composition of the BLM complex during unperturbed S-phase and identified a direct physical interaction with the Mcm6 subunit of the minichromosome maintenance (MCM) complex. Using distinct binding sites, BLM interacts with the N-terminal domain of Mcm6 in G1 phase and switches to the C-terminal Cdt1-binding domain of Mcm6 in S-phase, with a third site playing a role for Mcm6 binding after DNA damage. Disruption of Mcm6-binding to BLM in S-phase leads to supra-normal DNA replication speed in unperturbed cells, and the Helicase activity of BLM is required for this increased replication speed. Upon disruption of BLM/Mcm6 interaction, repair of replication-dependent DNA double-strand breaks is delayed and cells become hypersensitive to DNA damage and replication stress. Our findings reveal that BLM not only plays a role in the response to DNA damage and replication stress, but that its physical interaction with Mcm6 is required in unperturbed cells, most notably in S-phase as a negative regulator of replication speed.

  • cellular defects caused by hypomorphic variants of the Bloom Syndrome Helicase gene blm
    Molecular Genetics & Genomic Medicine, 2016
    Co-Authors: Vivek M Shastri, Kristina H Schmidt
    Abstract:

    Background Bloom Syndrome is an autosomal recessive disorder characterized by extraordinary cancer incidence early in life and an average life expectancy of ~27 years. Premature stop codons in BLM, which encodes a DNA Helicase that functions in DNA double-strand-break repair, make up the vast majority of Bloom Syndrome mutations, with only 13 single amino acid changes identified in the Syndrome. Sequencing projects have identified nearly one hundred single nucleotide variants in BLM that cause amino acid changes of uncertain significance. Methods and Results Here, in addition to identifying five BLM variants incapable of complementing certain defects of Bloom Syndrome cells, making them candidates for new Bloom Syndrome causing mutations, we characterize a new class of BLM variants that cause some, but not all, cellular defects of Bloom Syndrome. We find elevated sister-chromatid exchanges, a delayed DNA damage response and inefficient DNA repair. Conversely, hydroxyurea sensitivity and quadriradial chromosome accumulation, both characteristic of Bloom Syndrome cells, are absent. These intermediate variants affect sites in BLM that function in ATP hydrolysis and in contacting double-stranded DNA. Conclusion Allele frequency and cellular defects suggest candidates for new Bloom Syndrome causing mutations, and intermediate BLM variants that are hypomorphic which, instead of causing Bloom Syndrome, may increase a person's risk for cancer or possibly other Bloom-Syndrome-associated disorders, such as type-2 diabetes.

William K. Holloman - One of the best experts on this subject based on the ideXlab platform.