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

Up to two thirds of the total mutations detected in tumours are caused by inaccurate DNA replication. Our laboratory studies the process of DNA replication using a combination of biochemistry, cell biology and mouse genetics. Our current interests include: (1) the genetic and epigenetic elements that define replication origins; (2) the cellular responses to replicative stress (RS) caused by endogenous elements (e.g. natural decay of DNA; collisions between replication and transcription proteins) or exogenous factors such as UV radiation or DNA-damaging chemical agents. One of the responses to RS is the activation of ‘dormant’ origins, whose regulation remains poorly understood; (3) the mechanisms that limit DNA replication to only one round in each cell cycle, and the physiological consequences of their malfunction; and (4) the role of PrimPol, a recently characterised enzyme with primase and polymerase activities, in the ‘tolerance’ mechanisms that enable replication through damaged DNA.

Publications

• 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-.
• 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 (in press).
• 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 (in press).
• 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-.
• 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-.
• 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.
• 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.
• 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.
• Muñoz S, Méndez J (2017). DNA replication stress: from molecular mechanisms to human disease.. Chromosoma 126, 1-15.
• 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.
• 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.
• 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 Communications 7, 10660-.
• 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.
• Muñoz S, Méndez J (2016). DNA replication stress: from molecular mechanisms to human disease.. Chromosoma (in press).
• 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.
• 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.
• 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.
• 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.
• 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 Communications 6, 8548-.
• Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, Alvarez S, Diolaiti ME, Ugarte F, Forsberg EC, Le Beau MM, Stohr BA, Méndez J, Morrison C, Passegué E (2014). Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells.. Nature 512, 198-202.
• López-Contreras AJ, Ruppen I, Nieto-Soler M, Murga M, Rodriguez- Acebes S, Remeseiro S, Rodrigo-Perez S, Rojas AM, Mendez J, Muñoz J, Fernandez-Capetillo O (2013). A proteomic characterization of factors enriched at nascent DNA molecules.. Cell Reports 3, 1-12.
• García-Gómez S, Reyes A, Martínez-Jiménez MI, Chocrón ES, Mourón S, Terrados G, Powell C, Salido E, Méndez J, Holt IJ, Blanco L (2013). PrimPol, an archaic primase/polymerase operating in human cells.. Mol Cell 52, 541-553.
• Mourón S, Rodriguez-Acebes S, Martínez-Jiménez MI, García-Gómez S, Chocrón S, Blanco L, Méndez J (2013). Repriming of DNA synthesis at stalled replication forks by human PrimPol.. Nat Struct Mol Biol 20, 1383-1389.