Jeannette A. Hovsepian 1, @ and John H. Frenster 2, @
Departments of 1 Radiology and 2 Medicine,
Stanford University School of Medicine, Stanford, California 94035, USA
@ Present Addresses: RNA Research, Physicians' Educational
Series, Atherton, CA 94027-5446, USA
Phone: 650/367-6483; FAX: 650/364-1773,
e-mail: frensasc@ix.netcom.com
Supported in part by a USPHS Research Career Development Award CA-17857
to J.H.F.
The DNA Strand-Separation model of mammalian gene regulation (1)
is based on the ability of DNA and RNA sequences to interact during the
initiation and elongation phases of selective DNA transcription. RNA-DNA
helices are more stable than DNA-DNA helices, and RNA-RNA helices are still
more stable (2). Activator RNA is capable of binding
to complementary DNA sequences in the anti-template DNA strand, and by
such binding is capable of opening the DNA-DNA helix at selective sites
for the initiation of DNA transcription on the DNA-template strand. As
premessenger RNA is synthesized on the DNA-template strand, RNA splicing
results in the formation of excised RNA exons, RNA introns, and RNA 5'
leader sequences (3). Such excised 5' leader RNA sequences
are the complement of the activator RNA sequences that initiated the transcription
process. When DNA transcription is excessive at a particular gene locus,
rising levels of messenger RNA and of 5' leader RNA from that locus are
produced by the splicing process. Such increased levels of 5' leader RNA,
specific for the given gene locus, are now capable of binding to activator
RNA at the gene locus. Since RNA-RNA helices are more stable than DNA-RNA
helices, activator RNA may be removed from the anti-template DNA strand
at the gene locus. Such loss of activator RNA from the gene locus may result
in a decrease of DNA transcription at that locus, thus providing a feedback-loop
for the control of RNA synthesis at a particular gene locus. The RNA-RNA
complex formed by such feedback may be very stable, and may be capable
of storage during oogenesis, passage to daughter cells during mitosis,
or transport to other nearby cells during embryonic induction (4).
Figure 1:
RNA-Induced Chromatin Remodeling
and DNA Melting during Selective Gene Transcription (1, 2).
Figure 1:
Small nuclear RNA antisense
species function as de-repressors of transcription by displacing repressor
proteins (dark blocks), and then binding to the DNA anti-template
strand at an initiation site (Fig. 1). This initiation
stage frees the DNA template strand for transcription to gene-specific
pre-messenger sense RNA, following the recruitment to that site,
of RNA polymerase II and other transcription factors such as TFIIH.
A specific de-repressor RNA sequence may interact with complementary anti-template DNA sequences at several gene loci, permitting one anti-sense RNA sequence population to activate multiple genes synchronously.
An excessive synthesis of gene-specific pre-messenger sense RNA may result in formation of RNA-RNA duplexes between the anti-sense activator RNA and the 5’ leader sequences of that pre-messenger sense RNA, removing the activator RNA from that initiation site, and reducing the pre-messenger RNA synthesis at that site in a feedback mechanism controlling selective gene dosage.
Activator RNA binds to the anti-template strand of the selected DNA
locus, permitting transcription of gene-specific pre-messenger RNA (Fig.
2). The activator RNA of a given locus is complementary in base sequence
to the 5' leader portion of the pre-messenger product. The pre-messenger
RNA is spliced to form messenger RNA and 5' leader RNA . Splicing can occur
directly or after formation of an inactive duplex RNA by base-pairing of
activator RNA with the 5' leader. By such duplex formation, activator RNA
may be selectively removed from the DNA locus, thus providing feedback
inhibition
of transcription of the DNA locus. With continued consumption of messenger
RNA and degradation of 5' leader RNA, activator RNA may then be released
from the inactive duplex, thus providing a positive feedback
activation
of transcription of the DNA locus. Different coding and non-coding genes
may share 5' leaders with common base sequences, and thus be equally sensitive
to a given species of activator RNA, both during selective gene transcription
and during its selective inhibition (3).
Links to RNA and Biological Causality:
Links to
Euchromatin Activator RNA Reviews:
Links to
Euchromatin Activator RNA Research:
Links to Ultrastructural
Probes of DNase I-Sensitive Sites:
Links to
RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma
Immuno-Pathology:
Links to Activated
T-Lymphocyte Immunotherapy:
Links to Medical
Systems Biology:
Links to Selective
Gene Transcription:
Links to RNA-Induced
Epigenetics:
Links to RNA-Induced
Embryogenesis:
Links to RNA and
Biological Causality:
Links to Reprogramming
and Neoplasia:
A Brief History of Activator RNA:
"Ultrastructural
Probes of Active DNA Sites, and the RNA Activators of DNA". (PowerPoint
Presentation).