TY - JOUR
T1 - Nuclear localization of human DNA mismatch repair protein exonuclease 1 (hEXO1)
AU - Knudsen, Nina Østergaard
AU - Nielsen, Finn Cilius
AU - Vinther, Lena
AU - Bertelsen, Ronni
AU - Holten-Andersen, Steen
AU - Liberti, Sascha Emilie
AU - Hofstra, Robert
AU - Kooi, Krista
AU - Rasmussen, Lene Juel
PY - 2007
Y1 - 2007
N2 - Human exonuclease 1 (hEXO1) is implicated in DNA mismatch repair (MMR) and mutations in hEXO1 may be associated with hereditary nonpolyposis colorectal cancer (HNPCC). Since the subcellular localization of MMR proteins is essential for proper MMR function, we characterized possible nuclear localization signals (NLSs) in hEXO1. Using fluorescent fusion proteins, we show that the sequence 418KRPR421, which exhibit strong homology to other monopartite NLS sequences, is responsible for correct nuclear localization of hEXO1. This NLS sequence is located in a region that is also required for hEXO1 interaction with hMLH1 and we show that defective nuclear localization of hEXO1 mutant proteins could be rescued by hMLH1 or hMSH2. Both hEXO1 and hMLH1 form complexes with the nuclear import factors importin beta/alpha1,3,7 whereas hMSH2 specifically recognizes importin beta/alpha3. Taken together, we infer that hEXO1, hMLH1 and hMSH2 form complexes and are imported to the nucleus together, and that redundant NLS import signals in the proteins may safeguard nuclear import and thereby MMR activity.
AB - Human exonuclease 1 (hEXO1) is implicated in DNA mismatch repair (MMR) and mutations in hEXO1 may be associated with hereditary nonpolyposis colorectal cancer (HNPCC). Since the subcellular localization of MMR proteins is essential for proper MMR function, we characterized possible nuclear localization signals (NLSs) in hEXO1. Using fluorescent fusion proteins, we show that the sequence 418KRPR421, which exhibit strong homology to other monopartite NLS sequences, is responsible for correct nuclear localization of hEXO1. This NLS sequence is located in a region that is also required for hEXO1 interaction with hMLH1 and we show that defective nuclear localization of hEXO1 mutant proteins could be rescued by hMLH1 or hMSH2. Both hEXO1 and hMLH1 form complexes with the nuclear import factors importin beta/alpha1,3,7 whereas hMSH2 specifically recognizes importin beta/alpha3. Taken together, we infer that hEXO1, hMLH1 and hMSH2 form complexes and are imported to the nucleus together, and that redundant NLS import signals in the proteins may safeguard nuclear import and thereby MMR activity.
KW - Adaptor Proteins, Signal Transducing
KW - Animals
KW - Cell Line
KW - Cell Nucleus
KW - DNA Mismatch Repair
KW - DNA Repair Enzymes
KW - Exodeoxyribonucleases
KW - Humans
KW - Karyopherins
KW - Mice
KW - MutS Homolog 2 Protein
KW - Nuclear Localization Signals
KW - Nuclear Proteins
U2 - 10.1093/nar/gkl1166
DO - 10.1093/nar/gkl1166
M3 - Journal article
C2 - 17426132
SN - 0305-1048
VL - 35
SP - 2609
EP - 2619
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 8
ER -
