Titia Sixma Group

Titia Sixma

Oncode Investigator at NKI

My Research

Titia K. Sixma received her Ph.D. training in the group of Wim Hol at Groningen University determining crystal structures of a bacterial protein toxin homolog of cholera toxin, LT and she worked as a post-doctoral fellow in the group of Paul Sigler at Yale University. Currently she is group leader (since 1994) and head of the division of Biochemistry (since 2008) at the Netherlands Cancer Institute in Amsterdam. She uses structural biology/biochemistry and biophysical analysis to study the regulation of cellular signaling processes. The group is particularly interested in the proteins involved in ubiquitin conjugation and DNA mismatch repair. Since 2004 she has a part-time appointment as professor at the ErasmusMC in Rotterdam.

Titia Sixma is interested in the regulation of genome maintenance. Her approach is mechanistic, using high resolution methods in well-defined systems, that allow quantitative analysis and high resolution detail, thus providing insight in specific function and regulation, thus yielding important insights for drug development. She focusses particularly on the role of ubiquitin signalling and DNA mismatch repair

Major breakthroughs include the elucidation of DNA mismatch repair conformational states and the structure solution of AChBP, the first Cys-loop receptor ligand binding domain structure. More recent highlights were the elucidation of a novel chromatin mark on H2A after DNA damage, the definition of allosteric regulatory mechanisms for deubiquitinating enzymes and the characterization of specificity in ubiquitin E3 ligases DNA damage response and LUBAC.


  • 2008: Elected member of the KNAW (Royal Netherlands Academy of Arts and Sciences)
  • 2008:Elected member of Academiae Europaea
  • 2004: Elected member of EMBO
  • 1994: NVBMB Prize

Key Publications

  1. Faesen, A. C., Dirac, A. M., Shanmugham, A., Ovaa, H., Perrakis, A., & Sixma, T. K. (2011). Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase. Molecular cell, 44(1), 147-159.
  2. Groothuizen, F. S., Winkler, I., Cristovao, M., Fish, A., Winterwerp, H. H., Reumer, A., ... & Lebbink, J. H. (2015). MutS/MutL crystal structure reveals that the MutS sliding clamp loads MutL onto DNA. Elife, 4.
  3. Mattiroli, F., Vissers, J. H., van Dijk, W. J., Ikpa, P., Citterio, E., Vermeulen, W., ... & Sixma, T. K. (2012). RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell, 150(6), 1182-1195.
  4. Sahtoe, D. D., Van Dijk, W. J., Ekkebus, R., Ovaa, H., & Sixma, T. K. (2016). BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nature communications, 7, 10292.
  5. Sahtoe, D. D., van Dijk, W. J., El Oualid, F., Ekkebus, R., Ovaa, H., & Sixma, T. K. (2015). Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G. Molecular cell, 57(5), 887-900.
Contact Information
Titia Sixma Oncode Investigator

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