Group leader: Dr. Thomas G. Hofmann

Deutsches Krebsforschungszentrum

Im Neuenheimer Feld 280

69120 Heidelberg

phone: +49 6221 42 46 31

email: t.hofmann@dkfz-heidelberg.de

Cellular Senescence, Aging & DNA damage

Cellular senescence, a genetically controlled program arresting cell division, is activated in most cells after passing a limited proliferative capacity. Cancer cells override the senescence program and thus acquire an unlimited proliferative potential.

The molecular mechanisms triggering cellular senescence largely overlap with conserved cellular signalling pathways, which get activated in response to DNA damage. The elucidation of these DNA damage signalling pathways and the identification of novel signal transducers is a main focus of our work. In this context we have a particular interest in DNA damage-responsive kinases (ATM, HIPK2), tumor supressor p53 and PML nuclear bodies (PML-NBs). Our goal is to yield insight in the molecular mechanisms controlling DNA damage-induced cell fate-decision making between DNA repair, cellular senescence and cell death, in order to define potential molecular targets to manipulate cell fate decision-making, cancer cell responsiveness and cell aging.

Research Projects

a) Regulation of the apoptosis versus senescence decision

b) Function of PML-NBs

c) Function and regulation of p53 and HIPK2

a) Regulation of the apoptosis versus senescence decision

The DNA damage response (DDR) is essential for the maintenance of genome stability, and a dysfunctional DDR provokes genomic instability, a driving force for premature aging and cancer. When a cell faces DNA damage (e.g. by irradiation, reactive oxygen species, shortened telomeres, chemotherapeutic drugs), an evolutionary conserved signaling network is activated, which coordinates the cellular response to DNA damage. Dependent of divergent cellular effector pathways leading to DNA repair, apoptosis or cellular senescence. How the cellular decision-making between these divergent cell fate options is regulated at the molecular level remains largely unclear.

To gain insight in the DNA damage-induced effector pathway decision-making, we have used protein-protein interaction screens and RNA Seq to identify potential novel regulators of the DDR. We currently characterize their function in cell fate decision-making upon DNA damage. Ultimately, we aim at channeling the DDR towards a specific cell fate decision by manipulating selective molecular players.

b) Role of PML-NBs

The nucleus of a mammalian cell is organized in multiple nuclear domains, which include the heterogeneous family of nuclear bodies (NBs).

Promyelocytic leukemia nuclear bodies (PML-NBs) appear as distinct spherical structures in the cell nucleus and are found in virtually all mammalian cells. PML-NBs form multi-protein complexes and their number, size and protein composition dramatically changes in response to DNA damage, chemotherapeutic drug treatment, oncogenic transformation, cytokine signaling and viral infection. We are interested in understanding the biological function of PML-NBs and the underlying molecular mechanisms.

Various tumor suppressor proteins, including p53, CBP, HIPK2 and the DNA damage-responsive kinase ATM, are recruited upon genotoxic stress to PML-NBs. Accordingly, PML-NBs play an important role in stress-induced cell fate decisions.

c) Function and regulation of p53 and HIPK2

p53 is the most frequently mutated gene in human cancer and plays an essential role in tumor suppression and cell fate regulation after cellular stress. The evolutionary conserved serine/threonine kinase and tumor suppressor Homeodomain-interacting protein kinase 2 (HIPK2) is an important cell fate regulator and directly activates the apoptosis-inducing function of p53. Similar to what is known for p53, tumor cells also tend to inactivate HIPK2 function through different mechanisms, involving HIPK2 downregulation and mislocalization.
Using protein-protein interaction sreens we identified novel p53 and HIPK2 interacting proteins, which are currently functionally characterized. Using this approach, we aim at getting novel insight in the molecular mechanisms of cell fate control in normal cells and cancer cells.

Complete list of publications

Group members:

Sonja Matt (Postdoc)

Matthias Meister (PhD student)

Magdalena Liebl (PhD student)

Bojana Kriznik (PhD student)

Sandhya Balasubramanian (Master student)

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