DNA Replication Group

Juan Méndez Group Leader
T +34 917328000 (Ext 3490)
jmendez@cnio.es

Staff Scientists

Susana Llanos
Sara Rodríguez

Graduate Students

Elena Blanco
Daniel González
Patricia Ubieto

Technicians

Sara San José

Our laboratory studies the process of genome duplication, which is responsible for many of the mutations and genomic alterations found in human cancer. While the protein machinery responsible for DNA replication is normally very accurate, it becomes error-prone when the DNA displays chemical alterations caused by endogenous reactive species, external drugs or ionising radiation. We are interested in the phenomenon of replicative tolerance, i.e. the mechanisms that allow the progression of the ‘replisome’ proteins through damaged DNA, a step that normally precedes the activation of specific DNA repair pathways. In 2019, we focused on two major areas: (1) studying the efficiency of replication origins in response to replication stress in pluripotent cells, in the context of their three-dimensional positions in the nuclear chromatin; and (2) evaluating the function of DNA primase PrimPol in the tolerance of cytotoxic DNA lesions in normal and cancer cells with different genetic backgrounds.

Publications

Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, Collado M (2019). Identification and characterization of Cardiac Glycosides as senolytic compounds.. Nat Commun 10, 4731. CNIO Publication. Open Access
Llanos S, Megias D, Blanco-Aparicio C, Hernández-Encinas E, Rovira M, Pietrocola F, Serrano M (2019). Lysosomal trapping of palbociclib and its functional implications. Oncogene 38, 3886-3902. CNIO Publication.
Lafarga V, Sung HM, Haneke K, Roessig L, Pauleau AL, Bruer M, Rodriguez-Acebes S, Lopez-Contreras AJ, Gruss OJ, Erhardt S, Mendez J, Fernandez-Capetillo O, Stoecklin G (2019). TIAR marks nuclear G2/M transition granules and restricts CDK1 activity under replication stress. EMBO Rep 20, e46224. CNIO Publication.
Díaz-Talavera A, Calvo PA, González-Acosta D, Díaz M, Sastre-Moreno G, Blanco-Franco L, Guerra S, Martínez-Jiménez MI, Méndez J, Blanco L (2019). A cancer-associated point mutation disables the steric gate of human PrimPol. Sci Rep 9, 1121. CNIO Publication. Open Access
Quinet A, Tirman S, Jackson J, Švikovic S, Lemaçon D, Carvajal-Maldonado D, González-Acosta D, Vessoni AT, Cybulla E, Wood M, Tavis S, Batista LFZ, Méndez J, Sale JE, Vindigni A. (2019). PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells.. Mol Cell 77, 461-474. CNIO Publication.
Lafarga V, Sung H-M, Haneke K, Roessig L, Pauleau A-L, Bruer M, Rodríguez-Acebes S, López-Contreras A, Gruss OJ, Erhardt S, Méndez J, Fernández-Capetillo O, Stoecklin G (2019). TIAR controls mitotic entry, maintains genome stability and retains CDK1 in checkpoint bodies.. EMBO Rep 20, pii: e46224. CNIO Publication.
Jodkowska K, Pancaldi V, Almeida R, Rigau M, Graña-Castro O, Fernández-Justel JM, Rodríguez-Acebes S, Rubio-Camarillo M, Carrillo-de Santa Pau E, Pisano D, Al-Sharhrour F, Valencia A, Gómez M, Méndez J (2019). Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins.. bioRxiv (in press). CNIO Publication.
Pérez-Olivares M, Trento A, Rodriguez-Acebes S, González-Acosta D, Fernández-Antorán D, Román-García S, Martinez D, López-Briones T, Torroja C, Carrasco YR, Méndez J, Moreno de Alborán I (2018). Functional interplay between c-Myc and Max in B lymphocyte differentiation. EMBO Rep 19, e45770. CNIO Publication.
Rodriguez-Acebes S, Mourón S, Méndez J (2018). Uncoupling fork speed and origin activity to identify the primary cause of replicative stress phenotypes. J Biol Chem 293, 12855-12861. CNIO Publication.
Muñoz S, Búa S, Rodríguez-Acebes S, Megías D, Ortega S, de Martino A, Méndez J (2017). In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias. Cell Reports 19, 928-938. CNIO Publication.
Garzón J, Rodríguez R, Kong Z, Chabes A, Rodríguez-Acebes S, Méndez J, Moreno S, García-Higuera I. (2017). Shortage of dNTPs underlies altered replication dynamics and DNA breakage in the absence of the APC/C cofactor Cdh1.. Oncogene 36, 5808-5818. CNIO Publication.
Muñoz S, Méndez J (2017). DNA replication stress: from molecular mechanisms to human disease.. Chromosoma 126, 1-15. CNIO Publication.
Hernández-Pérez S, Cabrera E, Amoedo H, Rodríguez-Acebes S, Koundrioukoff S, Debatisse M, Méndez J, Freire R (2016). USP37 deubiquitinates Cdt1 and contributes to regulate DNA replication. Mol Oncol 10, 1196-1206. CNIO Publication. Open Access
Muñoz S, Méndez J (2016). DNA replication stress: from molecular mechanisms to human disease.. Chromosoma (in press). CNIO Publication.
Boskovic J, Bragado-Nilsson E, Saligram Prabhakar B, Yefimenko I, Martínez-Gago J, Muñoz S, Méndez J, Montoya G (2016). Molecular architecture of the recombinant human MCM2-7 helicase in complex with nucleotides and DNA.. Cell Cycle 15, 2431-2440. CNIO Publication.
Lecona E, Rodriguez-Acebes S, Specks J, Lopez-Contreras AJ, Ruppen I, Murga M, Muñoz J, Mendez J, Fernandez-Capetillo O (2016). USP7 is a SUMO deubiquitinase essential for DNA replication.. Nat Struct Mol Biol 23, 270-277. CNIO Publication.
Murga M, Lecona E, Kamileri I, Díaz M, Lugli N, Sotiriou SK, Anton ME, Méndez J, Halazonetis TD, Fernandez-Capetillo O (2016). POLD3 Is Haploinsufficient for DNA Replication in Mice. Mol Cell 63, 877-883. CNIO Publication.
Ahuja AK, Jodkowska K, Teloni F, Bizard AH, Zellweger R, Herrador R, Ortega S, Hickson ID, Altmeyer M, Mendez J, Lopes M (2016). A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells. Nat Commun 7, 10660. CNIO Publication. Open Access
Alvarez S, Díaz M, Flach J, Rodriguez-Acebes S, López-Contreras AJ, Martínez D, Cañamero M, Fernández-Capetillo O, Isern J, Passegué E, Méndez J (2015). Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality. Nat Commun 6, 8548. CNIO Publication. Open Access
Búa S, Sotiropoulou P, Sgarlata C, Borlado, LR, Eguren M, Domínguez O, Ortega S, Malumbres M, Blanpain C, Méndez J (2015). Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle.. Cell Cycle 14, 3897-3907. CNIO Publication.
Trakala M, Rodríguez-Acebes S, Maroto M, Symonds CE, Santamaría D, Ortega S, Barbacid M, Méndez J, Malumbres M (2015). Functional reprogramming of polyploidization in megakaryocytes. Dev Cell 32, 155-167. CNIO Publication.
Jacome A, Gutierrez-Martinez P, Schiavoni F, Tenaglia E, Martinez P, Rodríguez-Acebes S, Lecona E, Murga M, Méndez J, Blasco MA, Fernandez-Capetillo O (2015). NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity.. EMBO J 34, 2604-2619. CNIO Publication.