Chromatin, cancer and the ubiquitin system
Each cell cycle the DNA in the cell is copied through the process of DNA replication to transmit the genetic information to the daughter cells. However, every round of replication is also challenged by endogenous obstacles as well as alterations induced by exogenous agents in the DNA that can hamper a faithful copy of the DNA. The cell relies on multiple DNA repair pathways to prevent the acquisition of mutations and, in particular, the replication stress response is essential for cell viability since it stabilizes stalled replication forks and restarts the replication of DNA. Post-translational modifications play a central role in the control of DNA replication and repair. We are interested in understanding how the ubiquitin and SUMO pathways modulate DNA replication and the replication stress response beyond their role in protein stability. We want to unravel the mechanisms through which ubiquitin and SUMO control chromatin metabolism to ensure the stability of our genome.
Genomic instability is a hallmark of cancer that enables the uncontrolled proliferation of transformed cells but, at the same time, makes cancer cells especially sensitive to agents that induce replication stress. We want to understand how the ubiquitin and SUMO pathways work in the context of malignant transformation and to explore their use as potential targets for the development of new therapies. At the moment we are focused on the role of SUMO in breast cancer induced by mutations in BRCA1 and other defects in the machinery of DNA repair by homologous recombination. Finally, we are also working in the development of new tools and strategies to use the ubiquitin pathway for cancer treatment. We are interested in the design of Proteolysis Targeted Chimeras (PROTACs) using inhibitors of chromatin enzymes to target them for degradation for cancer treatment.
Figure 1. Ubiquitin-SUMO equilibrium during DNA replication. Replication forks are enriched in SUMOylated proteins and devoid of ubiquitinated factors. We are interested in understanding the regulation of DNA replication and repair by ubiquitin and SUMO.
Figure 2. Defects in Homologous Recombination and Cancer. Mutations in Homologous Recombination proteins lead to the accumulation of genomic alterations and the development of breast cancer, among others. Homologous recombination defects also increase replication stress in these tumors. We are exploring the use of VCP and SUMO inhibitors for the treatment of HR deficient tumors through their action on the replication stress response.
- Galarreta A*, Lecona E*, Valledor P, Ubieto P, Lafarga V, Fernández-Capetillo O. “USP7 couples DNA replication termination to mitotic entry” bioRxiv (2018) doi:https://doi.org/10.1101/305318. *Equal contribution. Co-corresponding author
- Lecona E, Fernández-Capetillo O. “Targeting ATR in Cancer” Nature Reviews Cancer (2018) 18: 586-595
- Mayor-Ruiz C, Olbrich T, Drosten M, Lecona E, Vega-Sendino M, Ortega S, Dominguez O, Barbacid M, Ruiz S, Fernandez-Capetillo O. “ERF deletion rescues RAS deficiency in mouse embryonic stem cells” Genes & Development (2017) 32: 568-576
- Lecona E, Fernández-Capetillo O. “An equilibrium of SUMO and Ubiquitin during DNA replication” Bioessays (2016) 38: 1209-17
- Nieto-Soler M, Morgado-Palacin I, Lafarga V, Lecona E, Murga M, Callen E, Azorin J, Alonso J, López-Contreras AJ, Nussenzweig A, Fernandez-Capetillo O. “Efficacy of ATR inhibitors as single agents in Ewing Sarcoma” Oncotarget (2016) 13: 58759-67.
- Murga M, Lecona E, Kamileri I, Lugli N, Sotiriou S, Días M, Antón ME, Méndez J, Halazonetis T, Fernández-Capetillo O. “POLD3 is haploinsufficient for DNA replication in mice” Molecular Cell (2016) 63: 877-83.
- Lecona E, Rodríguez-Acebes S, Specks J, López-Contreras A, Ruppen I, Murga M, Muñoz J, Méndez J, Fernández-Capetillo O. “USP7 is a SUMO deubiquitinase essential for DNA replication” Nature Structural & Molecular Biology (2016) 23: 270-7 Co-corresponding author
- Lecona E, Narendra V, Reinberg D. “USP7 cooperates with SCML2 to regulate the activity of PRC1” Molecular and Celullar Biology (2015) 35: 1157-68.
- Lecona E, Fernández-Capetillo O. “Replication Stress and Cancer: It Takes Two to Tango” Experimental Cell Research (2014) 329: 26-34.
- Bonasio R*, Lecona E*, Narendra V, Voigt P, Parisi F, Kruger Y, Reinberg D. “Interactions with RNA direct the Polycomb group protein SCML2 to chromatin where it represses target genes” *Equal contribution. eLife (2014) 3:
- Lecona E, Rojas LA, Bonasio R, Johnston A, Fernández-Capetillo O, Reinberg D. “Polycomb protein SCML2 regulates the cell cycle by binding and modulating CDK/CYCLIN/p21 complexes” PLoS Biology (2013) 11: e1001737.
- Bonasio, R., Lecona, E., Reinberg, D. “MBT domains in development and disease” Seminars in Cellular and Developmental Biology (2010) 21:221-230.