DNA Replication Group

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

Staff Scientists

Susana Llanos
Sara Rodríguez

Post-Doctoral Fellows

Estrella Guarino
Sergio Muñoz

Graduate Students

Elena Blanco
Roberto Masdemont
Sergi Roig
Patricia Ubieto

The process of DNA replication is responsible for many of the genomic alterations underlying the activation of oncogenes or the inactivation of tumour suppressor genes. While some of these alterations are inherent to life, e.g. the introduction of mutations due to DNA polymerase errors, others are caused by environmental agents – UV light, ionising radiation, toxic chemicals in tobacco smoke, and other pollutants – that induce chemical modifications in the DNA and complicate its replication. The capacity to generate difficult-to-replicate DNA modifications, e.g. covalent links between the two strands of the double helix, is the basis for the cytotoxic effect of cisplatin and other drugs used in cancer therapy. Our laboratory studies how the ‘replisome’ machinery is capable of operating through these lesions, a step that normally leads to the activation of specific DNA repair pathways. In 2020 we focused on the study of the PrimPol enzyme that mediates the replicative tolerance of DNA crosslinks generated by common chemotherapy agents.

Publications

González-Acosta D, Blanco-Romero E, Ubieto-Capella P, Mutreja K, Míguez S, Llanos S, García F, Muñoz J, Blanco L, Lopes M, Méndez J (2021). PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks. EMBO J 40, e106355. CNIO Publication.
Calvo PA, Martínez-Jiménez MI, Díaz M, Stojkovic G, Kasho K, Guerra S, Wanrooij S, Méndez J, Blanco L. (2021). Motif WFYY of human PrimPol is crucial to stabilize the incoming 3′-nucleotide during replication fork restart. Nucleic Acids Res 49, 8199-8213. CNIO Publication.
Morales C, Ruiz-Torres M, Rodríguez-Acebes S, Lafarga V, Rodríguez-Corsino M, Megías D, Cisneros DA, Peters JM, Méndez J, Losada A (2020). PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection. J Biol Chem 295, 146-157. 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. (2020). PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells.. Mol Cell 77, 461-474. CNIO Publication.
Piberger AL, Bowry A, Kelly RDW, Walker AK, González-Acosta D, Bailey LJ, Doherty AJ, Méndez J, Morris JR, Bryant HE, Petermann E (2020). PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts. Nat Commun 11, 5863. CNIO Publication. Open Access
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
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