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

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 scree...

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Bibliographic Details
Published in:Nature communications Vol. 5; no. 1; p. 5437
Main Authors: Ziv, Omer, Zeisel, Amit, Mirlas-Neisberg, Nataly, Swain, Umakanta, Nevo, Reinat, Ben-Chetrit, Nir, Martelli, Maria Paola, Rossi, Roberta, Schiesser, Stefan, Canman, Christine E., Carell, Thomas, Geacintov, Nicholas E., Falini, Brunangelo, Domany, Eytan, Livneh, Zvi
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 25.11.2014
Nature Publishing Group
Nature Pub. Group
Subjects:
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13/89
14
14/1
14/19
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14/63
38
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38/77
631/337/1427/2354
631/67/1990/283/1897
631/80/86
Cell Line
Deoxyribonucleic acid
DNA
DNA Damage - radiation effects
DNA Repair
DNA Replication - radiation effects
DNA-Directed DNA Polymerase - genetics
DNA-Directed DNA Polymerase - metabolism
Humanities and Social Sciences
Humans
Lesions
Leukemia
Leukemia, Myeloid, Acute - enzymology
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - metabolism
multidisciplinary
Mutation
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Protein Binding
Science
Science (multidisciplinary)
Ultraviolet Rays
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Cells cope with replication-blocking DNA lesions by translesion DNA synthesis (TLS) polymerases, including polη. Here, the authors show that NPM1 , a gene frequently mutated in acute myeloid leukaemia, protects polη from proteasomal degradation, and that NPM1 deficiency causes a TLS defect.
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ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms6437