Sequence and transcriptional study ofHNRPKpseudogenes, and expression and molecular modeling analysis of hnRNP K isoforms

Abstract

The heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a large family of proteins that play important roles in telomere biogenesis, DNA repair, cellular signaling, and the regulation of expression at both the transcriptional and translational levels. One of the most extensively studied hnRNP family members, hnRNP K, has been implicated in a variety of processes, including chromatin remodeling, transcription, splicing, and translation events. In this study, we analyzed processed HNRPK pseudogenes (HNRPK ψ1–ψ4) and coding sequences. HNRPK pseudogenes are apparently nonfunctional, and ψ1 might correspond to transcripts from an ancestral gene. Phylogenetic and sequence analyses suggest that HNRP genes arose by duplication, and that new structural and sequence features expanded the functions of hnRNPs. The expression analysis of hnRNP K isoforms showed that isoform a is expressed in normal testis and in non-small cell lung cancer (NCI-H1155 NSCLC cell line), although the shorter isoform (isoform b) is expressed in different tumor cell lines (IM9 B-lymphoblastoid, Hs578T human breast cancer epithelial, T98G human glioma cell lines). Using molecular modeling, we obtained KH1 and KH3 models, which pointed to important residues for DNA–protein binding and no structural differences between isoforms a and b. To our knowledge, this is the first phylogenetic study including vertebrate HNRP genes and HNRPK pseudogenes, and the first report comparing the KH1 and KH3 domains of isoforms a and b of the hnRNP K protein. New investigations in tumor samples must be done to validate the differential expression observed here. The results shown are important because the hnRNP K protein might represent a new target for pharmacologic intervention in virus replication and cancer.