Oncotarget. 2014 Sep; 5(18): 80398051.

Regulatory roles of LINE-1-encoded reverse transcriptase in cancer onset and

progression
Ilaria Sciamanna,1 Alberto Gualtieri,1 Pier Vincenzo Piazza,2 and Corrado Spadafora1
1
Istituto Superiore di Sanit, Rome, Italy
2
NeuroCentre Magendie, INSERM U862, Univ Bdx2, Bordeaux, France
Abstract
LINE-1 retrotransposons encode the reverse transcriptase (RT) enzyme, required for their own
mobility, the expression of which is inhibited in differentiated tissues while being active in tumors.
Experimental evidence indicate that the inhibition of LINE-1-derived RT restores differentiation in
cancer cells, inhibits tumor progression and yields globally reprogrammed transcription profiles.
Newly emerging data suggest that LINE-1-encoded RT modulates the biogenesis of miRNAs, by
governing the balance between the production of regulatory double-stranded RNAs and RNA:DNA
hybrid molecules, with a direct impact on global gene expression. Abnormally high RT activity
unbalances the transcriptome in cancer cells, while RT inhibition restores normal miRNA profiles
and their regulatory networks. This RT-dependent mechanism can target the myriad of transcripts both coding and non-coding, sense and antisense - in eukaryotic transcriptomes, with a profound
impact on cell fates. LINE-1-encoded RT emerges therefore as a key regulator of a previously
unrecognized mechanism in tumorigenesis
LINE-1 elements are the largest family of human retrotransposons, mobile genetic elements that
move in the human genome via an RNA intermediate. The LINE-1 family comprises about 500.000
copies, collectively accounting for as much as 17% of the human genome

Que es la transcripcin y tipos de polimerasas en eucariotes

El RNA tiene Uracilo en lugar de Timina

Forma de apareamiento del Uracilo con Adenina

Estructura secundaria de RNA (apareamiento U)

Estructura secundaria de RNA (tRNA)

Concepto de promotor, sitio de inicio de la transcripcin y factor

de iniciacin sigma en bacterias (necesario para reconocer
promotor)

Secuencias consenso de promotores en procariotes

Orientacin del templado de DNA y de

su transcrito (Sntesis 5 3 sobre
templado 3 5

Factores generales de transcripcin en

eucariotes y caja TATA, Tata binding
protein, fosforilacin del carboxi
terminal de RNA-polimerasa como
condicin de inicio de la transcripcin

General transcription factors (GTFs) bind to specific sequence elements in the promoter. These elements (the B
recognition element (BRE), the TATA box (TATA), the initiator (Inr), the motif ten element (MTE) and the
downstream promoter element (DPE)) and their approximate locations relative to the transcription start site (TSS,
black arrow) are shown2.
(Tomado de Nature , autores: Nicholas J. Fuda, M. Behfar Ardehali & John T. Lis Nature 461, 186-192(10
September 2009)

Secuencias consenso en eucariotes

Transcrito primario

mRNA

El pre-mRNA
-Qu es el cap
-Qu es poli-A, dnde se encuentra y tamao promedio.
-Concepto de regin codificante y regin no-codificante.
El 5' cap y Poli-A tienen entre sus principales funciones:
Cap ---regulacin de exportacin nuclear.
Cap----previene la degradacin por exonucleasas-------poliA tambin (3).
Cap----promueve la traduccin /PoliA tambin.

Detalle qumico
de la estructura
del Cap: unin 5a
5 y grupo
metilado en
Guanina

Detalle del capeado

In the human genome, Myc is located on chromosome 8 and

is believed to regulate expression of 15% of all genes
through binding on Enhancer Box sequences (E-boxes) and
recruiting histone acetyltransferases (HATs). This means that
Myc also functions to regulate global chromatin structure by
regulating histone acetylation.
Malfunctions in Myc have been
found in carcinoma of the cervix,
colon, breast, lung and stomach.
Myc is thus viewed as a promising
target for anti-cancer drugs.
The c-myc gene is translocated to
one of the immunoglobulin loci in
virtually all Burkitt's lymphomas

The gene for factor VIII is located on Xq28

Recordatorio de presencia de intrones y exones

Forma de remocin de los intrones, secuencias consenso ataque

interno por Adenina con formacin de lazo de vaquero

Splicing alternativo da lugar a variantes de tropomiosina

hnRNP =(heterogeneous
nuclear ribonucleoprotein)
CBC= Cap Binding Complex
SR= Serine-Arginine rich
splicing factors
En azul los exones

Impresin general de un complejo de splicing llamado spliceosoma

U1, U2 son snRNP (small nuclear ribonucleoproteins)

El Spliceosoma es un complejo formado por cinco

ribonucleoprotenas nucleares pequeas o snRNP (complejo
formado por unas diez protenas ms una pequea molcula de
ARN)

mRNA
Salida del ncleo de verdadero mRNA con Cap (retencin de
protenas nucleares), unin del Cap a protena citoslica (eIF),
interaccin de poli-A con Cap por otra proteina (eIF)

En el ncleo tambin se forman los

componentes del ribosoma, entre los
cuales hay RNAs, por tanto se requiere
de transcripcin. El RNA ribosomal
tambin madura por un proceso
anlogo al splicing
Hay tambin transcripcin de otro
tipo de RNA que puede reducir la
expresin gentica por ser
parcialmente complementario al
mRNA (o al DNA). Es decir, los
MicroRNAs (miRNA; que son de
21-22 bases) y se encuentran en
eucariotes y actan por un proceso
llamado RNA interference
(RNAi)

TRADUCCIN

Figure 7-27 Essential Cell Biology ( Garland Science 2010)

Aminoacil-tRNA sintetasa

Semejanza estructural entre el factor de liberacin RF y tRNA

Atomic structure and hierarchical assembly of a cross- amyloid

bril (2013) Fitzpatrick et al PNAS vol. 110, no. 14, pages 5468
5473.

RESUMEN DE EVENTOS
TRANSCRIPCINTRADUCCIN