Chromatin Mobility and Genome Integrity

The Lottersberger laboratory studies the molecular pathways that encompass DNA Damage Response (DDR) signaling, with the ultimate goal of developing tools for the diagnosis and tailored treatment of cancer.

The integrity of our DNA is continuously threatened by both endogenous and exogenous sources of damage, which have the potential to give rise to mutations and chromosome rearrangements.  Eukaryotic cells have evolved DNA Damage Response (DDR) pathways to recognize and repair such damage.  The crucial role these pathways play is evidenced by the links between defects in DDR proteins and genome instability, tumorigenesis, and cancer progression.  However, defects in DNA repair pathways also provide a therapeutic window that has been successfully exploited by many clinical cancer treatments, such as Topoisomerase Inhibitor (Irinotecan) for metastatic colon/rectal cancer and PARP inhibitor (Olaparib and Rubraca) for ovarian cancer.

One of the most dangerous DNA lesions is a DNA Double Strand Break (DSB), in which the backbones of the duplex DNA strands are simultaneously broken.  Unrepaired DSBs threaten cell survival by altering transcription, replication, and chromosome segregation.  Moreover, the inappropriate repair of multiple DSBs can result in chromosome translocations, a key step in the initial stages of tumorigenesis.  Using various cellular systems to generate proximal and distal DSBs, we recently showed that increased chromatin mobility promotes the mis-repair of multiple distal DSBs, revealing the fundamental importance of controlled chromatin dynamics to accurate DNA repair. 

We are combining mouse genetics and quantitative time-lapse imaging to dissect the principles of chromatin dynamics and understand its contribution to DNA repair, tumorigenesis and ageing. We also aim to investigate the mechanisms that regulate mobility, identify new molecular factors involved in regulating chromatin dynamics, and to evaluate the consequences of altered mobility on genome integrity in both normal and cancer cells.

Research

About me

Curriculum Vitae

  • Master degree University of Milano-Bicocca, Italy - 2002
  • Ph.D. University of Milano-Bicocca, Italy – 2006
  • Post-doc University of Milano-Bicocca, Italy - 2006
  • Post-doc The Rockefeller University, NY, USA - 2017

Publications

  1. Lottersberger F., Karssemeijer R.A., Dimitrova N. and de Lange T. (2015). 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 2015 Nov 5;163(4):880-93. Featured Article
  2. Zimmermann M., Lottersberger F., Buonomo S.B., Sfeir A. and de Lange T. (2013). 53BP1 regulates DSB repair using Rif1 to control 5' end resection. Science 2013 Feb 8;339(6120):700-4.
  3. Lottersberger F.*, Bothmer A.*, Robbiani D.F., Nussenzweig M.C. and de Lange T. (2013). Role of 53BP1 oligomerization in regulating double-strand break repair. Proc. Natl Acad Sci U S A Feb 5;110(6):2146-51. 
    * equal contribution.
  4. Lottersberger F., Panza A., Lucchini G. and Loghese MP. (2007). Functional and physical interactions between yeast 14-3-3, acetyltransferase and deacetylase proteins in response to DNA replication stress” Mol. Cell. Biol. May;27(9):3266-81.
  5. Lottersberger F., Panza A., Piatti S., Lucchini G. and Loghese MP. (2006). The Saccharomyces cerevisiae 14-3-3 Proteins Are Required for the G1/S Transition, Actin Cytoskeleton Organization and Cell Wall Integrity” Genetics Jun;173(2):661-75.
  6. Clerici M., Baldo V., Mantiero D., Lottersberger F., Lucchini G. and Longhese MP. (2004). A Tel1/MRX-dependent checkpoint inhibits the metaphase-to-anaphase transition after UV irradiation in the absence of Mec1. Mol Cell Biol. Dec; 24(23):10126-44. 
  7. Lottersberger F., Rubert F., Baldo V., Lucchini G. and Loghese MP. (2003). Functions of Saccharomyces cerevisiae 14-3-3 proteins in response to DNA damage and to DNA replication stress. Genetics Dec;165(4):1717-32.

Organisation