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

Author

Listed:
  • Omer Ziv

    (Weizmann Institute of Science)

  • Amit Zeisel

    (Weizmann Institute of Science)

  • Nataly Mirlas-Neisberg

    (Weizmann Institute of Science)

  • Umakanta Swain

    (Weizmann Institute of Science)

  • Reinat Nevo

    (Weizmann Institute of Science)

  • Nir Ben-Chetrit

    (Weizmann Institute of Science)

  • Maria Paola Martelli

    (Institute of Hematology, University of Perugia)

  • Roberta Rossi

    (Institute of Hematology, University of Perugia)

  • Stefan Schiesser

    (Ludwig Maximilians University Munich)

  • Christine E. Canman

    (University of Michigan)

  • Thomas Carell

    (Ludwig Maximilians University Munich)

  • Nicholas E. Geacintov

    (New York University)

  • Brunangelo Falini

    (Institute of Hematology, University of Perugia)

  • Eytan Domany

    (Weizmann Institute of Science)

  • Zvi Livneh

    (Weizmann Institute of Science)

Abstract

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 two-stage 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-η (polη), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of polη. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in ~30% of AML patients results in excessive degradation of polη. 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.

Suggested Citation

  • Omer Ziv & Amit Zeisel & Nataly Mirlas-Neisberg & Umakanta Swain & Reinat Nevo & Nir Ben-Chetrit & Maria Paola Martelli & Roberta Rossi & Stefan Schiesser & Christine E. Canman & Thomas Carell & Nicho, 2014. "Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6437
    DOI: 10.1038/ncomms6437
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