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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Nature communications Jg. 5; H. 1; S. 5437
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 25.11.2014
Nature Publishing Group
Nature Pub. Group
Schlagworte:
13
13/106
13/109
13/31
13/89
14
14/1
14/19
14/34
14/63
38
38/47
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-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
content type line 14
ObjectType-Feature-2
content type line 23
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms6437