Chromatin, cancer and the ubiquitin system

Fas Associated Factor 1 (FAF1) is a protein involved in the regulation of apoptosis playing an essential role in development. In addition, it acts as an adaptor of the AAA+ ATPase VCP/p97 through the binding of ubiquitylated and SUMOylated proteins during S phase. We have described that FAF1 mediates the actions of VCP/p97 to maintain the ubiquitin/SUMO landscape in chromatin and to sustain DNA replication. Recently, FAF1 has been identified as a tumor suppressor in colon cancer. The deletion of FAF1 in a cellular model leads to reduced apoptosis but the consequences on DNA replication remain unexplored. In this project we will study the consequences of the loss of FAF1 in a colon cancer cellular model. The student will analyze the dynamics of S phase progression and DNA replication in the absence of FAF1, the sensitivity to the generation of replication stress and to the inhibition of VCP/p97 in this model.

We offer a position to carry out the TFM on this topic. Selected publications:

• Rodríguez-Acebes S, Martín-Rufo R, Fernández-Llorente A, de la Vega-Barranco G, Oroz P, Martín-Doncel E., Toledo LI, Méndez J, Lecona E. “VCP/p97 extracts DNA polymerase a/Primase to limit the activation of the replication stress response” bioRxiv (2022).
• Martín-Rufo R, de la Vega-Llorente G, Lecona E. “Ubiquitin and SUMO as molecular timers during DNA replication” Seminars in Cell and Developmental Biology doi: 10.1016/j.semcdb.2022.02.013 (2022)
• Franz V, Valledor P, Ubieto-Capella P, Pilger D, Galarreta A, Lafarga V, Fernández-Llorente A, de la Vega-Barranco G, den Brave F, Hoppe T, Fernández-Capetillo O, Lecona E. “USP7 and VCP^FAF1 define the SUMO/Ubiquitin landscape at DNA replication forks” Cell Rep (2021) 37: 109819.
• Galarreta A, Valledor P, Fernández-Capetillo O, Lecona E. “Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1” Int J Mol Sci (2021) 22: 8796.
• Galarreta A, Valledor P, Ubieto-Capella P, Lafarga V, Zarzuela E, Muñoz J, Malumbres M, Lecona E*, Fernández-Capetillo O. “USP7 limits CDK1 activity throughout the cell cycle” EMBO J (2021) 40:e99692 *Co-corresponding autor