TY - JOUR
T1 - Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin
AU - Ziv, Omer
AU - Zeisel, Amit
AU - Mirlas-Neisberg, Nataly
AU - Swain, Umakanta
AU - Nevo, Reinat
AU - Ben-Chetrit, Nir
AU - Martelli, Maria Paola
AU - Rossi, Roberta
AU - Schiesser, Stefan
AU - Canman, Christine E.
AU - Carell, Thomas
AU - Geacintov, Nicholas E.
AU - Falini, Brunangelo
AU - Domany, Eytan
AU - Livneh, Zvi
N1 - Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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-n (poln), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of poln. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in ∼30% of AML patients results in excessive degradation of poln. 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.
AB - 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-n (poln), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of poln. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in ∼30% of AML patients results in excessive degradation of poln. 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.
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U2 - 10.1038/ncomms6437
DO - 10.1038/ncomms6437
M3 - Article
C2 - 25421715
AN - SCOPUS:84923358777
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 5437
ER -