Identification of sequence determinants of human nuclear dUTPase isoform localization.

Abstract:

:dUTP nucleotidohydrolase (dUTPase) catalyzes the hydrolysis of dUTP to dUMP and pyrophosphate and is the central regulator of cellular dUTP pools. Nuclear (DUT-N) and mitochondrial (DUT-M) isoforms of the protein have been identified in humans and arise from the same gene by the alternative use of 5' exons. Recently, it has been shown that these isoforms are aberrantly expressed in some cancers and overexpression of dUTPase in the nucleus is associated with resistance to chemotherapeutic agents that target thymidylate biosynthesis. In this study, we have examined the signals necessary for dUTPase isoform localization using green fluorescent protein fusion constructs. We report that the N-terminal 23 amino acids of DUT-N are required but not sufficient for complete nuclear localization. Within this region, we identified a small cluster of basic residues (K(14)R(15)R(17)) that resemble a classic monopartite nuclear localization signal (NLS). Mutation of these residues completely abolishes nuclear localization. In addition, phosphorylation of Ser11 near the putative NLS has no affect on DUT-N nuclear localization. Through deletion analysis we show improved sorting of DUT-N to the nucleus when most of the protein sequence is present. Therefore, we conclude that DUT-N may contain a complex NLS that is located throughout the entire protein.

journal_name

Exp Cell Res

authors

Tinkelenberg BA,Fazzone W,Lynch FJ,Ladner RD

doi

10.1016/s0014-4827(03)00048-x

keywords:

subject

Has Abstract

pub_date

2003-07-01 00:00:00

pages

39-46

issue

1

eissn

0014-4827

issn

1090-2422

pii

S001448270300048X

journal_volume

287

pub_type

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