Another example is provided by miR-10a. 3 end processing, Genistein HSURs bind Sm proteins and are incorporated into ribonucleoprotein particles (RNPs) through the same biogenesis pathway (7). Functions have only been assigned to HSUR1 and HSUR2. These two viral snRNAs interact with host-encoded short regulatory ncRNAs called microRNAs (miRNAs) (8). miRNAs canonically function by binding to the 3 untranslated regions (3UTRs) of mRNAs to promote the degradation and diminished translation of target mRNAs (9). The specificity of miRNA:target interactions is usually dictated by the seed region (nucleotides 2C7) of the miRNA. miRNA expression can be specific, with some miRNAs exhibiting high tissue-specific expression while others showing ubiquitous expression (10). One miRNA can regulate multiple mRNAs in the same pathway, and several miRNAs can act cooperatively to regulate one target mRNA (9). In HVS-infected cells, HSUR1 interacts with miR-27 and HSUR2 interacts with miR-16, whereas the 5 end of both viral snRNAs interacts with miR-142-3p (Figure ?(Figure1).1). A second, functional isoform of miR-142-3p that lacks the 5 terminal U is co-expressed with miR-142-3p in lymphoid cells (11). This second isoform, or isomiR, of miR-142-3p, called miR-142-3p-1, is believed to arise from differential processing of the miR-142 primary transcript and displays a slightly different seed region. Hence, miR-142-3p-1 regulates targets through a largely discrepant set of binding sites (12). It is currently unknown if miR-142-3p-1 can also bind HSUR1 and HSUR2. These viral snRNA:miRNA interactions result in different functional outcomes. HSUR1 binds miR-27 family members in an unusual fashion. In addition to exhibiting complementarity to the seed region of miR-27, HSUR1 also exhibits extensive complementarity to the 3 region of the miRNA (Figure ?(Figure1).1). This kind of miRNA:target interaction results in the degradation of the miRNA by a process termed target RNA-directed miRNA Rabbit Polyclonal to TRIM24 degradation (TDMD) (13). The HSUR1:miR-27 interaction provided the first example of TDMD (8), a mechanism Genistein that is widely employed to regulate miRNA populations (14,15). Diminished abundance of Genistein miR-27 promotes the activation of the infected T cell and viral latency (16). The HSUR1:miR-142-3p interaction has not been experimentally validated and its functional role is unknown. Open in a separate window Figure 1. Interactions between HSUR1, HSUR2 and miRNAs. Sequences of HSUR1, HSUR2, miR-142-3p, miR-16?and miR-27 are shown. Binding sites for miRNAs and miRNA seed regions are highlighted in grey. Binding of miR-27 to HSUR1 results in TDMD (8), while miR-16 is used in HSUR2-mediated mRNA repression (17,18). Sm-binding sites are shown in black boxes. The HSUR2 region involved in interactions with mRNAs (18) is shown in a dashed box. HSUR2 does not affect the abundance or activity of miR-142-3p and miR-16 (17,18). Instead, HSUR2 functions as a miRNA adaptor that utilizes miR-142-3p and miR-16 to regulate host gene manifestation. HSUR2 basepairs with sponsor mRNAs and recruits these two sponsor miRNAs to destabilize target mRNAs. It was 1st demonstrated that miR-142-3p activity is required for repression of all HSUR2 target mRNAs whereas miR-16 activity is only required for the repression of a subset of target mRNAs (17). HVS utilizes HSUR2 to inhibit apoptosis in infected cells, and the activity of both miR-142-3p and miR-16 is required for HSUR2-mediated inhibition of this process (17). When HSUR2 function was first described, several mechanistic aspects remained unclear. For example, it was not understood how HSUR2 recognizes target mRNAs and why miR-142-3p is required for repression of all HSUR2 target mRNAs while miR-16 is required for repression of only a subset of focuses on. The recognition of sequences mediating relationships between HSUR2 and target mRNAs partially solved some of these questions (18). Most HSUR2 binding sites reside in the 3UTRs of target mRNAs, and most focuses on exhibit only one binding site for this viral snRNA. HSUR2 does not contain a subregion, or seed sequence, that is used for most HSUR2:mRNA interactions. Instead, an extensive region of HSUR2 (Number ?(Number1)1) is involved in interactions with target mRNAs, with different base-pairing plans employed in each HSUR2:mRNA interaction (18). Luciferase reporter-based analyses of individual HSUR2 binding sites exposed some unexpected results. HSUR2 shows base-pairing set up flexibility in relationships with each target mRNA since target mRNAs can be mutagenized.