Complexities associated with expression of Epstein-Barr virus (EBV) lytic origins of DNA replication

• Published in: Nucleic acids research Vol. 35; no. 10; pp. 3391 - 3406
• Main Authors: Xue, Shao-An, Griffin, Beverly E
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.05.2007; Oxford Publishing Limited (England)
• Subjects: Animals; Cell Line; DNA Replication; DNA, Viral - biosynthesis; Epstein-Barr virus; Gene Expression Regulation, Viral; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - metabolism; Herpesvirus 4, Human - physiology; Humans; Molecular Biology; Nuclease Protection Assays; Promoter Regions, Genetic; Replication Origin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Antisense - analysis; RNA, Messenger - biosynthesis; RNA, Messenger - chemistry; RNA, Viral - biosynthesis; RNA, Viral - chemistry; Transcription Initiation Site; Transcription, Genetic; Viral Proteins - biosynthesis; Viral Proteins - genetics; Virus Replication
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkm170

EBV has two lytic origins (oriLyt) of DNA replication lying at divergent sites on the viral genome within a duplicated sequence (DS). The latter contains potential hairpin loops, 'hinge' elements and the promoters for transcripts from viral genes BHLF1 and LF3. These genes themselves consist largely of 125 and 102 bp repetitive sequences, respectively, and encode basic proteins. We have examined these genomic regions in detail in attempts to understand why lytic replication--necessary for virus survival--is so inefficient, and to identify controlling elements. Our studies uncovered a diverse family of promoters (P) for BHLF1 and LF3, only one pair of which (P1) proved sensitive to chemical inducing agents. The others (P2-P3/4), abutting the replication 'core' origin elements in DS and extending into 5'-unique sequences, may play roles in the maintenance of viral latency. We further identified a family of overlapping small complementary-strand RNAs that transverse the replication 'core' origin elements in a manner suggesting a role for them as 'antisense' species and/or DNA replication primers. Our data are discussed in terms of alternative lytic replication models. We suggest our findings might prove useful in seeking better control over viral lytic replication and devising strategies for therapy.