Aberrant C-terminal domain of polymerase η targets the functional enzyme to the proteosomal degradation pathway

DNA Repair
Sana Ahmed-SeghirPatricia Kannouche

Abstract

Xeroderma pigmentosum variant (XP-V) is a rare genetic disease, characterized by sunlight sensitivity and predisposition to cutaneous malignancies. XP-V is caused by a deficiency in DNA polymerase eta (Polη) that plays a pivotal role in translesion synthesis by bypassing UV-induced pyrimidine dimers. Previously we identified a new Polη variant containing two missense mutations, one mutation within the bipartite NLS (T692A) and a second mutation on the stop codon (X714W) leading to a longer protein with an extra 8 amino acids (721 instead of 713 AA). First biochemical analysis revealed that this Polη missense variant was barely detectable by western blot. As this mutant is extremely unstable and is nearly undetectable, a definitive measure of its functional deficit in cells has not been explored. Here we report the molecular and cellular characterization of this missense variant. In cell free extracts, the extra 8 amino acids in the C-terminal of Polη(721) only slightly reduce the bypass efficiency through CPD lesions. In vivo, Polη(721) accumulates in replication factories and interacts with mUb-PCNA albeit at lower level than Polη(wt). XP-V cells overexpressing Polη(721) were only slightly UV-sensitive. Altogether, our data st...Continue Reading

References

Jan 1, 1975·Proceedings of the National Academy of Sciences of the United States of America·A R LehmannD Bootsma
Sep 1, 1995·Mutation Research·J P Volpe, J E Cleaver
Mar 20, 2003·The Journal of Biological Chemistry·Anne StaryAlain Sarasin
Dec 17, 2004·Journal of Cell Science·Tomoo OgiAlan R Lehmann
Mar 9, 2007·The Journal of Investigative Dermatology·Miki TaniokaChikako Nishigori
Aug 19, 2007·Molecular and Cellular Biology·Robert E JohnsonLouise Prakash
Sep 28, 2007·Proceedings of the National Academy of Sciences of the United States of America·Wei Yang, Roger Woodgate
Jul 3, 2008·Nature Reviews. Molecular Cell Biology·Karlene A Cimprich, David Cortez
Dec 30, 2008·Molecular Cell·Seung-Hwan Kim, W Matthew Michael
Dec 17, 2009·Molecular and Cellular Biology·Yong-Sam JungXinbin Chen
Feb 4, 2010·Human Molecular Genetics·Emmanuelle DesprasPatricia L Kannouche
Feb 18, 2010·Molecular Cell·Marzena BienkoIvan Dikic
Jul 28, 2011·Molecular and Cellular Biology·Yong-Sam JungXinbin Chen
Dec 20, 2011·The FEBS Journal·Franziska KriegenburgRasmus Hartmann-Petersen
Oct 19, 2012·Environmental and Molecular Mutagenesis·Emmanuelle DesprasPatricia L Kannouche
Mar 5, 2013·Cold Spring Harbor Perspectives in Biology·Julian E Sale
Jul 5, 2013·Expert Opinion on Therapeutic Targets·Min ShenQ Ping Dou

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Citations

Nov 5, 2016·Nature Communications·Emmanuelle DesprasPatricia L Kannouche
Sep 22, 2017·Nucleic Acids Research·Federica BertolettiSimone Sabbioneda

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