OncologyGenomic Instability and Cancer Laboratory

Genomic Instability and Cancer Laboratory

The recognition of many types of DNA lesions activates the cellular DNA damage response (DDR). The DDR orchestrates the appropriate cellular programs to maintain genome integrity after genotoxic stress. Defects in the DDR lead to genomic instability that is a characteristic of many rare human diseases, such as Ataxia telangiectasia and Seckel Syndrome. In addition, an active DDR is evident in many pre-cancerous and cancerous lesions and it has been proposed to act as an inducible barrier to malignancy. Understanding the signal transduction networks governed by the DDR, and the consequences of their impairment, will facilitate our understanding of tumor development and enhance cancer treatment strategies.

The goal of the research in our laboratory is to understand the underlying molecular mechanisms of human disease. We focus on the role of the DNA damage response (DDR) in preserving chromosomal stability, particularly during DNA replication, and study the impact of its impairment in the context of rare disease pathology and cancer. Moreover, we are interested in exploiting this knowledge to identify new targets and strategies for cancer therapy.

1. DNA replication and chromosomal stability: the role of the Tousled like kinases (TLKs).
The activity of TLK1 and TLK2 is controlled by the DDR. Both kinases have been implicated in the regulation of ASF1, a key histone chaperone. We are analyzing the regulation, substrates and functions of these kinases and their role in supporting cancer growth and maintaining genome stability.

2. DNA replication and differentiation: understanding the Geminin family proteins.
Geminin is a key regulator of DNA replication, ensuring it occurs once per cell cycle. We are studying the roles of 2 additional Geminin family members called GEMC1 and MCIDAS that both play dual roles in replication and transcription. We have identified a key role for GEMC1 in the differentiation of multiciliated cells and are investigating the impact of its loss on development and cancer.

3. Mechanisms of microcephaly in rare diseases.
Microcephaly is a component of many rare human diseases, some of which are associated with DDR defects and genome instability. We are examining the function of candidate microcephaly genes and elucidating the molecular events that lead to the loss of neural progenitors during development.


Figure legend: A. Loss of TLK2 leads to defects in placental development and embryonic death (Segura-Bayona et al, Cell Death and Diff. 2017). B. Depletion of TLK activity increases DNA damage in cancer cells. C. GEMC1 is required for the differentiation of multiciliated cells in the trachea and oviduct (Terre et al, EMBO J 2016). D. Loss of the Seckel Syndrome protein CEP63 leads to mitotic defects (far right panel), neural progenitor loss and microcephaly. Sections of the cortex are shown for comparison (Marjanovic et al, Nat. Comm. 2015).

Silva J, Aivio S, Knobel PA, Bailey LJ, Casali A, Vinaixa M, Garcia-Cao I, Coyaud É, Jourdain AA, Pérez-Ferreros P, Rojas AM, Antolin-Fontes A, Samino-Gené S, Raught B, González-Reyes A, Ribas de Pouplana L, Doherty AJ, Yanes O and Stracker TH.
Nat Cell Biol, 20 (2), 162-174 (2018)
Terré B, Piergiovanni G, Segura-Bayona S, Gil-Gómez G, Youssef SA, Attolini CS, Wilsch-Bräuninger M, Jung C, Rojas AM, Marjanović M, Knobel PA, Palenzuela L, López-Rovira T, Forrow S, Huttner WB, Valverde MA, de Bruin A, Costanzo V and Stracker TH.
Embo J, 35 (9), 942-60 (2016)
Pereira-Lopes S, Tur J, Calatayud-Subias JA, Lloberas J, Stracker TH and Celada A.
Blood, (2015)
Rein K, Yanez DA, Terré B, Palenzuela L, Aivio S, Wei K, Edelmann W, Stark JM and Stracker TH.
Nucleic Acids Res, 43 (15), 7371-87 (2015)
Marjanović M, Sánchez-Huertas C, Terré B, Gómez R, Scheel JF, Pacheco S, Knobel PA, Martínez-Marchal A, Aivio S, Palenzuela L, Wolfrum U, McKinnon PJ, Suja JA, Roig I, Costanzo V, Lüders J and Stracker TH.
Nat Commun, 6 7676 (2015)
Arroyo R, Suñé G, Zanzoni A, Duran-Frigola M, Alcalde V, Stracker TH, Soler-López M and Aloy P.
J Mol Biol, 427 (6 Pt B), 1436-50 (2015)
Chen WT, Ebelt ND, Stracker TH, Xhemalce B, Van Den Berg CL and Miller KM.
Elife, 4 (2015)
Zhen Y, Knobel PA, Stracker TH and Reverter D.
J Biol Chem, 289 (50), 34838-50 (2014)
Rein K and Stracker TH.
Exp Cell Res, 329 (1), 162-9 (2014)
Torres AG, Piñeyro D, Filonava L, Stracker TH, Batlle E and Ribas de Pouplana L.
Febs Lett, 588 (23), 4279-86 (2014)
Knobel PA, Belotserkovskaya R, Galanty Y, Schmidt CK, Jackson SP and Stracker TH.
Mol Cell Biol, 34 (11), 2062-74 (2014)
Bianchi J, Rudd SG, Jozwiakowski SK, Bailey LJ, Soura V, Taylor E, Stevanovic I, Green AJ, Stracker TH, Lindsay HD and Doherty AJ.
Mol Cell, 52 (4), 566-73 (2013)
Stracker TH, Roig I, Knobel PA and Marjanović M.
Front Genet, 4 37 (2013)
Foster SS, De S, Johnson LK, Petrini JH and Stracker TH.
P Natl Acad Sci Usa, 109 (25), 9953-8 (2012)

This group is financially supported by the following:

  • Ministerio de Economía y Competitividad (MINECO)
  • European Commission (EC), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa"


Group news & mentions

<p>Confocal microscopy shows co-localization of EXD2 (magenta) with the mitochondrial ribosome (yellow). DNA is stained to define the nucleus (cyan).</p>
16 Gen 2018

Barcelona, ​​16 de gener de 2018.- Investigadors del Laboratori d'Inestabilitat Genòmica i Càncer de l'Institut de Recerca Biomèdica (IRB Barcelona) han identificat EXD2 com un actor clau

<p>Cross sections of wild type or TLK2 deficient embryos stained for the proliferative marker Ki67. Embryos lacking TLK2 (left) appear morphologically normal but developmentally delayed. (S. Segura-Bayona, IRB Barcelona)</p>
18 Jul 2017

Diversos mitjans s'han fet ressò de la recerca de l'investigador de l'IRB Barcelona Travis H.

<p>This graphic image simulates the metabolic fluxes in cells, with the nutrients marked with a stable isotope that allow to study the fluxes and the transformation dynamics of these nutrients.</p>
23 Feb 2017

Un estudi publicat aquesta setmana a la revista científica Angewandte Chemie presenta una nova metodologia que esprem l'ús de la Ressonància Magnètica Nuclear (RMN) per estudiar el metabol

Upcoming events

25 Abr
Aula Fèlix Serratosa, Parc Científic de Barcelona
25 Abr
Aula Fèlix Serratosa, Parc Científic de Barcelona
Dr. Roland Le Borgne, Group leader, Institute of Genetics & Development of Rennes, France.
26 Abr
Aula Fèlix Serratosa, Parc Científic de Barcelona
Speaker: Dr. Montserrat Terrazas, Molecular modelling and bioinformatics - Structural & Computational Biology Programme, IRB Barcelona