14 research outputs found

    Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin

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    Cells cope with replication-blocking lesions via translesion DNA synthesis (TLS). TLS is carried out by low-fidelity DNA polymerases that replicate across lesions, thereby preventing genome instability at the cost of increased point mutations. Here we perform a twostage siRNA-based functional screen for mammalian TLS genes and identify 17 validated TLS genes. One of the genes, NPM1, is frequently mutated in acute myeloid leukaemia (AML). We show that NPM1 (nucleophosmin) regulates TLS via interaction with the catalytic core of DNA polymerase-eta (pol eta), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of pol eta. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in similar to 30% of AML patients results in excessive degradation of pol eta. These results establish the role of NPM1 as a key TLS regulator, and suggest a mechanism for the better prognosis of AML patients carrying mutations in NPM1

    Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin

    Get PDF
    Cells cope with replication-blocking lesions via translesion DNA synthesis (TLS). TLS is carried out by low-fidelity DNA polymerases that replicate across lesions, thereby preventing genome instability at the cost of increased point mutations. Here we perform a twostage siRNA-based functional screen for mammalian TLS genes and identify 17 validated TLS genes. One of the genes, NPM1, is frequently mutated in acute myeloid leukaemia (AML). We show that NPM1 (nucleophosmin) regulates TLS via interaction with the catalytic core of DNA polymerase-eta (pol eta), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of pol eta. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in similar to 30% of AML patients results in excessive degradation of pol eta. These results establish the role of NPM1 as a key TLS regulator, and suggest a mechanism for the better prognosis of AML patients carrying mutations in NPM1

    In Silico Investigation of Spice Molecules as Potent Inhibitor of SARS-CoV-2

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    The severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is a novel infectious disease that is in rapid growth. Several trials are going on worldwide to find a solution for this pandemic. The viral replication can be blocked by inhibiting the SARS-CoV-2 spike protein (SARS-CoV-2 Spro), and the SARS-CoV-2 main protease (SARS-CoV-2 Mpro). The binding of potential small molecules to these proteins can possibly inhibit the replication and transcription of the virus. The spice molecules that are used in our food have the properties of antiviral, antifungal, and antimicrobial nature. As spice molecules are consumed in the diet, hence its antiviral properties against SARS-CoV-2 will benefit in a significant manner. Therefore, in this work, the blind molecular docking of 30 selected spice molecules (through ADME property screening) was performed for the identification of potential inhibitors for the Spro and Mpro of SARS-CoV-2. We found that all the molecules bind actively with the SARS-CoV-2 Spro and Mpro. However, the molecule, Piperine, is found to have the highest binding affinity among the 30 screened molecules. We anticipate immediate wet-lab experiments and clinical trials in support of this computational study might be helpful in inhibiting the SARS-CoV-2 virus.</p

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    TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer

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    TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here, we show that TENT4A regulates multiple biological pathways and focuses on its multilayer regulation of translesion DNA synthesis (TLS), in which error-prone DNA polymerases bypass unrepaired DNA lesions. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase η and RAD18 E3 ligase, which guides the polymerase to replication stalling sites and monoubiquitinates PCNA, thereby enabling recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD and via the long non-coding antisense RNA PAXIP1-AS2, which had no known function. Knocking down the expression of TENT4A or CYLD, or overexpression of PAXIP1-AS2 led each to reduced amounts of the RAD18 protein and DNA polymerase η, leading to reduced TLS, highlighting PAXIP1-AS2 as a new TLS regulator. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and their TENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in this cancer
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