Veronique Smits

Research interest

Genomic instability occurs in most human cancers, and the accumulation of mutations in genes that regulate key processes like cell cycle division is the primary cause of the uncontrolled growth of tumour cells. In order to accurately preserve their genetic information, cells have evolved efficient checkpoint and repair mechanisms that deal with potentially lethal DNA lesions. These cellular processes of DNA damage sensing and repair are tightly linked to tumorigenesis in higher eukaryotes, as they are one of the first barriers of defence against cancer. Also markers of an activated DNA damage response (DDR) are expressed throughout different stages of cancer. Mammalian cells are particularly vulnerable to DNA damage caused by endogenous or exogenous sources during S phase. In fact, replicative stress is a known source of genomic instability in cancer.

Central in the DDR is the ATM/ATR signalling pathway, initially thought to merely function as a phosphorylation cascade. Studies in recent years demonstrate that also other post-translational modifications of signalling proteins and histones around the site of lesion are critical in this response. Examples are (mono- and poly-)ubiquitination, SUMOylation, acetylation, methylation etc.
My group aims to identify novel post-translational modifications important for the DDR in human cells, of chromatin components and other players in this pathway, and to study the function of this modification(s) for the response and molecular mechanism(s) underlying it. Our research focuses on ubiquitin hydrolases (DUBs) and chromatin modifying enzymes. Preliminary data show several potentially interesting candidates. In addition, the potential role of these enzymes as a way to modulate anti-cancer treatment will also be investigated.

Publications

  • Smits V.A.J., Freire R. (2016). USP7/HAUSP: A SUMO deubiquitinase at the heart of DNA replication. Bioessays 38: 863-868. doi: 10.1002/bies.201600096.

  • Choe K., Nicolae D., Constantin D., Kawasawa Y., Delgado-Diaz M.R., De S., Freire R., Smits V.A.J., Moldovan G.L. (2016). HUWE1 interacts with PCNA to alleviate replication stress. EMBO Rep. 17: 874-886. doi: 10.15252/embr.201541685.

  • Smits V.A.J. and Gillespie D.A. (2015). DNA damage control: regulation and functions of checkpoint kinase 1. FEBS J. 282: 3681-3692. doi: 10.1111/febs.13387.

  • Gong E.Y., Smits V.A.J., Fumagallo F., Piscitello D., Morrice N., Freire R., Gillespie D.A. (2015). KA1-targeted regulatory domain mutations activate Chk1 in the absence of DNA damage. Sci Rep. 5: 10856. doi: 10.1038/srep10856.

  • Alonso de Vega I., Martín Y. and Smits V.A.J. (2014) USP7 controls Chk1 protein stability by direct deubiquitination. Cell Cycle 13: 3921-3926. doi: 10.4161/15384101.2014.973324.

  • Smits V.A.J. and Gillespie D.A. (2014) Cancer therapy; targeting the poison within. Cell Cycle 13: 2330-2333. doi: 10.4161/cc.29756.

  • Delgado-Díaz M.R., Martín Y., Berg A., Freire R. and Smits V.A.J. (2014) Dub3 controls DNA damage signalling by direct deubiquitination of H2AX. Mol. Oncol. 8: 884-893. doi: 10.1016/j.molonc.2014.03.003.

  • Warmerdam D.O., Brinkman E.K., Marteijn J.A., Medema R.H., Kanaar R. and Smits V.A.J. (2013) UV-induced G2 checkpoint depends on p38 MAPK and minimal activation of ATR-Chk1 pathway. J. Cell Science 126: 1923-1930. doi: 10.1242/jcs.118265.

Active Grants

  • Regulation of the cellular response to DNA damage and replication stress: Molecular mechanisms and implications for tumorigenesis Spanish Ministry of Economy and Competitiveness (SAF2016-80626-R) Jan 2017 – Dec 2019, € 190,000.00

  • Preventing genome instability and cancer: Post-translational modifications in DNA replication control and the DNA damage response Spanish Ministry of Economy and Competitiveness (SAF2013-49149-R) Jan 2014 – June 2017, € 180,000.00

Group members

Group leader:
  • Veronique Smits
PhD students:
  • Ignacio Alonso de Vega
Technicians:
  • Cristina Paz
Undergraduates:
  • Ana Rodríguez