Biology Reference
In-Depth Information
HCMV establishes infection for the life of the host characterized by latent infection
with periodic reactivation for production and spread of infectious progeny. This
multifaceted life cycle of the herpesvirus requires an abundance of gene products
and regulatory elements that makes cytomegalovirus genomes one of the most
complex among human viruses. The defining characteristics of the cytomegalovirus
and the minimal impact on genome size afforded by miRNAs inform the logic of
virus-encoded miRNAs.
Abbreviations
miRNA: MicroRNA ; HCMV: Human cytomegalovirus ; EBV:
Epstein Bar Virus ; HSV: Herpes simplex virus ; miRISC: MicroRNA-induced
silencing complex; MHV 68: Murine gammaherpesvirus 68; RRV: Rhesus macaque
rhadinovirus ; rLCV: Rhesus lymphocryptovirus ; MDV: Marek's disease virus
Introduction
In 1993, the discovery of an approximately 22-nucleotide RNA (
lin-4
) responsible
for the posttranscriptional regulation of LIN-14 protein levels in
caenorhabditis
elegans
represented the beginnings of a paradigm shift in molecular biology (Lee
et al. 1993; Wightman et al. 1993). While
lin-4
was discovered in 1993, it was not
until 1999 that it was shown to inhibit protein synthesis after the initiation of trans-
lation (Olsen and Ambros 1999).
Lin-4
is the founding member of a family of small
RNAs, termed microRNAs (miRNA), that now number over 400 in humans
(Bentwich et al. 2005). Not 15 years after
lin-4
's discovery, it has been predicted
that over 30% of human gene products are subject to miRNA-mediated regulation
(Lewis et al. 2005).
miRNAs are endogenously encoded approximately 22-nt RNAs that are respon-
sible for the temporal and spatial regulation of gene products involved in diverse
cellular processes including development, apoptosis, differentiation, cell cycle reg-
ulation, and immune response (Ambros 2004; Taganov et al. 2006; O'Connell et al.
2007; Rodriguez et al. 2007; Taganov et al. 2007). Functionally, miRNAs mediate
gene silencing by guiding the miRNA-induced gene silencing complex (miRISC)
to target mRNAs (Tang 2005). Targeting of mRNA by miRISC leads to transla-
tional inhibition or cleavage of the targeted mRNA. The specificity of most animal
miRNA-target mRNA complexes is determined by complementarity of a seed
region, namely nucleotides 2-7 of the miRNA (Brennecke et al. 2005). When rec-
ognition of mRNA by miRNA is mediated primarily by the seed region, transla-
tional inhibition is typically the end result, while extensive sequence complementarity
between the miRNA and target mRNA results in cleavage of the target mRNA
(Ambros 2004). Complementary sequences in the target mRNA usually reside in
the 3′ UTR (Lewis et al. 2005). Due to the size of the seed region, miRNAs are
predicted to target as many as ten mRNAs. Additionally, multiple miRNAs may
target the same mRNA with the 3′-UTRs containing target sites for multiple miRNAs,
