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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Vydáno v:	Nature communications Ročník 5; číslo 1; s. 5437
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 25.11.2014 Nature Publishing Group Nature Pub. Group
Témata:	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
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	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