Download telomeres and telomerase group

Vice-Direction of Basic Research
TELOMERES AND
TELOMERASE GROUP
MOLECULAR ONCOLOGY PROGRAMME | TELOMERES AND TELOMERASE GROUP
Maria A. Blasco
Group Leader
Staff Scientists
Isabel López de Silanes, Rosa M.
Marión, Paula Martínez, Marinela
Méndez, Águeda M. Tejera, Elisa
Varela ( until May )
Post-Doctoral Fellow
Kurt Whittemore
Graduate Students
Leire Bejarano, Aksinya Derevyanko,
Lole Ferrara, Juan José Montero,
Miguel Ángel Muñoz, Juan Manuel
Povedano ( until June )
Technicians
Rosa M. Serrano, Nora Soberón ( until
June ) ( TS )*
Student in practice
Ana C. Moises da Silva
*Titulado Superior ( Advanced Degree )
OVERVIEW
We study the mechanisms by which tumour cells are immortal
and normal cells are mortal. Immortality is one of the most
universal characteristics of cancer cells. The enzyme telomerase
is present in more than 95% of all types of human cancers and
absent in normal cells in the body. Telomeres are nucleoprotein
complexes located at the ends of chromosomes, essential for
chromosome protection and genomic stability. Progressive
shortening of telomeres associated with organism ageing leads
to ageing. When telomeres are altered adult stem cells have a
maimed regenerative capacity.
“ We have demonstrated that TERRA
long non-coding RNAs are essential
for telomere protection.”
Our research aims are :
ɗɗ Generating mouse models to validate telomeres and
telomerase as therapeutic targets for cancer and age-related
diseases.
ɗɗ Deciphering the interplay between telomeres and DNA repair
pathways.
ɗɗ Studying the role and regulation of non-coding telomeric
RNAs or TERRA.
ɗɗ Testing telomerase gene therapy in ‘ telomere syndromes ’
and age-related diseases.
ɗɗ Elucidating the role of telomerase and telomeres in adult stem
cell biology and in nuclear reprogramming of differentiated
cells to iPS cells.
ANNUAL REPORT 2016
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SPANISH NATIONAL CANCER RESEARCH CENTRE, CNIO
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Vice-Direction of Basic Research
MOLECULAR ONCOLOGY PROGRAMME | TELOMERES AND TELOMERASE GROUP
Figure 2 The genomic origin of
telomeric RNAs ( TERRA ). Both in mice
and in humans, TERRA arise from one
or at most two loci.
RESEARCH HIGHLIGHTS
Figure 1 Representative image of an
eye of chimaeric mice. Cells bearing
hyper-long telomeres are visualised in
green. Telomeres appear in red.
Fighting aplasic anaemia using a therapy designed
to delay ageing
Aplasic anaemia is a rare, potentially fatal disease of the blood,
by which the bone marrow is unable to generate blood cells at the
appropriate pace. The disease can be hereditary or acquired and
develops at any stage of life. A subgroup of the inherited form is
caused by replicative impairment of haematopoietic stem and
progenitor cells owing to very short telomeres due to mutations
in telomerase and other telomere components. An abnormal
telomere shortening is also described in cases of acquired aplasic
anaemia. We have tested the efficacy of our telomerase gene
therapy, originally designed to delay ageing, in two independent
mouse models of aplasic anaemia due to short telomeres. We
found that a high dose targets the bone marrow compartment,
including haematopoietic stem cells. Telomerase treatment
following telomere attrition in bone marrow cells rescues aplasic
anaemia and mouse survival. Improved survival is associated
with a significant increase in telomere length in peripheral
blood and bone marrow cells, as well as improved blood counts.
Our telomerase gene therapy represents a novel therapeutic
strategy to treat aplasic anaemia provoked or associated with
short telomeres.
Mice with hyper-long telomeres and unaltered genes
Telomere length is genetically determined, but in the past we
were able to generate mouse embryonic stem ( ES ) cells with
telomeres twice the size of normal ones. We have now used
ANNUAL REPORT 2016
such ES cells with ‘ hyper-long ’ telomeres, traceable thanks
to the co-expression of green fluorescent protein ( GFP ), to
generate chimaeric mice containing cells with both hyper-long
and normal telomeres. We showed that chimaeric mice contain
GFP-positive cells – bearing hyper-long telomeres – in all mouse
tissues ( FIGURE 1 ), display normal tissue histology, as well
as normal survival. Both hyper-long and normal telomeres
shorten with age, but GFP-positive cells manage to retain longer
telomeres as the mice age. These chimaeric mice also accumulate
fewer cells with short telomeres and less DNA damage with age,
and express lower levels of p53. Cells with hyper-long telomeres
are longitudinally maintained or enriched with age in highly
renewing compartments ( i.e. blood ). We demonstrated that
mice with functional, longer and better preserved telomeres
can be generated without the need for genetic manipulations,
such as telomerase overexpression.
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Telomeric RNAs are essential to maintain telomeres
Despite their especially compact structure, which is difficult to
access, telomeres transcribe information like the rest of the DNA
generating long non-coding RNAs known as TERRA. Deciphering
the role of TERRA was one of the unsolved issues of telomere
biology in the past decade. This was, in part, due to a lack of
knowledge on the TERRA loci, which had prevented functional
genetic studies. We had already shown that mouse TERRA arise
mainly from the subtelomere of chromosome 18 and to a lesser
extent from the subtelomere of chromosome 9. We have now
described that long non-coding RNAs with TERRA features are
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TERRA. Thus, both in mice and in humans, TERRA arise from
one, or at most two loci ( FIGURE 2 ). Ablation of 20q-TERRA in
human cells results in a dramatic loss of telomere sequences and
in the induction of a massive DNA damage response. These latter
findings represent the first demonstration, in any organism, of
the essential role of TERRA in the maintenance of telomeres. s
transcribed from the human 20q and Xp subtelomeres. We used
the CRISPR-Cas9 technology to delete the 20q locus, which
resulted in a dramatic decrease in TERRA levels. The deletion of
the Xp locus, on the contrary, does not lead to decreased TERRA
levels. These findings demonstrate that, although human TERRA
arise from two loci, the 20q locus is the main origin of human
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PUBLICATIONS
Mosteiro L, Pantoja C, Alcázar N, Marión
RM, Chondronasiou D, Rovira M, Fernández-Marcos PJ, Muñoz-Martin M, Blanco-Aparicio C, Pastor J, Gómez-López
G. de Martino A, Blasco MA, Abad M,
Serrano M ( 2016 ). Tissue damage and
senescence provide critical signals for
cellular reprogramming in vivo. Science
354, 6315. pii : aaf4445.
Fernández-Alvira JM, Fuster V, Dorado B,
Soberón N, Flores I, Gallardo M, Pocock
S, Blasco MA, Andrés V ( 2016 ). Short telomere load, telomere length, and subclinical atherosclerosis : The PESA Study. J Am
Coll Cardiol 67, 2467-2476.
Montero JJ, López de Silanes I, Graña
O, Blasco MA ( 2016 ). Telomeric RNAs
are essential to maintain telomeres. Nat
Commun 7, 12534.
Varela E, Muñoz-Lorente MA, Tejera AM,
Ortega S, Blasco MA ( 2016 ). Generation
of mice with longer and better preserved
telomeres in the absence of genetic manipulations. Nat Commun 7, 11739.
Bär C, Povedano JM, Serrano R, Benitez-Buelga C, Popkes M, Formentini I,
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Bobadilla M, Bosch F, Blasco MA ( 2016 ).
Telomerase gene therapy rescues telomere length, bone marrow aplasia and
survival in mice with aplasic anaemia.
Blood 127, 1770-1779.
Aguado T, Gutiérrez FJ, Aix E, Schneider
RP, Giovinnazo G, Blasco MA, Flores I
( 2016 ). Telomere length defines the cardiomyocyte differentiation potency of
mouse induced pluripotent stem cells.
Stem Cells. PMID : 27612935.
Benitez-Buelga C, Vaclová T, Ferreira S,
Urioste M, Inglada-Perez L, Soberón, N,
Blasco MA, Osorio A, Benitez J ( 2016 ).
Molecular insights into the OGG1 gene, a
cancer risk modifier in BRCA1 and BRCA2
mutations carriers. Oncotarget 7, 2581525825.
Martínez P, Gómez-López G, Pisano DG,
Flores JM, Blasco MA ( 2016 ). A genetic
interaction between RAP1 and telomerase
reveals an unanticipated role for RAP1 in
telomere maintenance. Aging Cell. PMID :
27586969.
Boskovic J, Martínez-Gago J, Mendez-Pertuz M, Buscato A, Martínez-Torrecuadrada
JL, Blasco MA ( 2016 ). Molecular Architecture of Full Length TRF1 Favors its
SPANISH NATIONAL CANCER RESEARCH CENTRE, CNIO
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Interaction with DNA. J Biol Chem 291,
21829-21835.
Comino-Méndez I, Tejera ÁM, Currás-Freixes M, Remacha L, Gonzalvo P,
Tonda R, Letón R, Blasco MA, Robledo M,
Cascón A ( 2016 ). ATRX driver mutation in
a composite malignant pheochromocytoma. Cancer Genet 209,272-277.
Bär C, Blasco MA ( 2016 ). Telomeres and telomerase as therapeutic targets to prevent
and treat age-related diseases. F1000Research 5, pii : F1000 Faculty Rev-89.
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scriptase-based therapies for treatment
of conditions associated with myocardial
infarction. WO/2016/020346.
Bobadilla M, Formentini I, Blasco MA, Baer
C, Bosch I Tubert F ( 2016 ). Telomerase
reverse transcriptase-based therapies.
WO/2016/020345.
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AWARDS AND RECOGNITION
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PATENTS
Blasco MA, Bernardes B, Bosch F, Ayuso E ( 2016 ). Telomerase reverse transcriptase for protection against aging.
EP2402038B1.
Flores I, Canela A, Blasco MA ( 2016 ).
Methods for the determination of telomere length in a semi-automatic manner
of every single cell in an immobilized cell
population. CA2723950.
Blasco MA, Bernardes de Jesus B, Baer
C, Serrano Ruiz MR, Bosch I Tubert F,
Ayuso E, Formentini I, Bobadilla M, Mizrahi J ( 2016 ). Telomerase reverse tran-
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Miguel Catalán Career Achievement
Award, Regional Government of Madrid.
Scientific Committee Member, Innovative
Medicines Initiative 2 ( IMI2 ) Joint Undertaking, Brussels, Belgium.
Member of the External Scientific Board
of Instituto de Investigación Sanitaria y
Biomédica de Alicante ( ISABIAL ), Alicante, Spain.
Member, Alumni Advisory Board, Universidad Autónoma de Madrid.
Founding Editor, Cell Stress.
Editorial Board Member, Nutrition &
Healthy Aging.
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