Hepatitis B virus (HBV) DNA polymerase (P) is translated from a bicistronic pregenomic RNA via a ribosomal leaky scanning mechanism. Another viral transcript, the preC RNA, differs from pregenomic RNA by the presence of some 30 nt at the 5' end that encompass the preC initiation codon. This RNA is used exclusively for expression of the precore protein which is a precursor of secreted HBeAg. Factors leading to inefficient translation of the P and C proteins from the preC RNA were explored using a genetic approach in transient transfection assays. Our data indicate that when translating the precore protein, the elongation arrest that occurs during targeting of nascent polypeptide chains to the endoplasmic reticulum interferes with the scanning of the 40S ribosomal subunits. Such interference seems to hinder initiation of the ribosomes at the downstream genes. Furthermore, the presence of the preC initiator codon in the preC mRNA has resulted in a reduction in the number of scanning ribosomes reaching the C and P initiator codons compared with the case of pregenomic RNA. Finally, although the preC initiator codon is in a suboptimal context for translation initiation, an RNA secondary structure, the encapsidation signal, located downstream to the initiator codon is shown to enhance codon recognition, resulting in a depletion of the number of 40S ribosomal subunits available for scanning of the downstream AUG codons. This study demonstrates that the HBV encapsidation signal plays an additional role in facilitating recognition of the preC initiator codon.


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