Biochemie-Zentrum der Universität Heidelberg (BZH)

Michael Brunner
Goal
A quantitative understanding of how the cir-
cadian clock measures time on a molecular
level, how the endogenous clock is synchro-
nized with the astronomical day and how it
directs the temporal organization of global
gene expression.
Background
Circadian clocks are almost ubiquitous time keeping
devices that organize physiology and behavior
in anticipation of daily environmental changes associated
with earth`s rotation. On the molecular
level circadian clocks are cell-autonomous oscillatory
systems that modulate rhythmic expression
of a large number of genes. The circadian clocks
are synchronized with the exogenous day by environmental
cues such as light and temperature. In
the absence of entraining cues clock oscillations
persist with an intriguingly precise period that creates
an endogenous robust self-sustained subjective
day-night rhythm of approximately 24 h.
Circadian clocks in eukaryotes are based on
networks of interconnected transcriptional, translational
and post-translational feedback loops.
These networks are organized in similar fashion
in fungi (Neurospora), insects (Drosophila) and
vertebrates (mouse and human). In the core of
circadian oscillators are PAS domain-containing
6 Michael Brunner
1988 PhD, University of Heidelberg, Germany
1989-1991 Post Doc at Princeton University and Rockefeller Research
Laboratory, New York, USA (James E. Rothman)
1992-1998 Group Leader and habilitation at University of Munich
(Walter Neupert)
1998-2000 Professor (C3 interim) University of Munich
since 2000 Full Professor at the Heidelberg University Biochemistry
Center (BZH)
The Molecular Clock of Neurospora crassa
transcription factors that are the master transcriptional
activators of clock-controlled genes
(ccg’s). Specific sets of ccg’s encode factors that
inhibit their respective PAS domain activators and
thereby establish negative feedback loops. The
negative feedback loops are interconnected with
positive loops in which the negative elements
support expression and accumulation of the positive
elements.
Post-translational modification of positive and
negative clock components regulate their subcellular
localization, interaction, activity and turnover,
leading to a circadian activity and abundance
rhythm of the transcriptional activators, which
in turn results in rhythmic transcription of ccg’s.
Some ccg’s encode transcription factors that
regulate subsets of ccg’s on a secondary level.
Approximately 10% of the genes in eukaryotes
are transcribed under control of the clock.
The core components of the interconnected feedback
loops of the clock of Neurospora crassa
are the transcription factors WHITE COLLAR-1
(WC-1) and WC-2 and their negative regulator
FREQUENCY (FRQ). A number of factors, in particular
kinases and phosphatases, are critical or
even essential for the FRQ/WCC oscillator, but
these components are rather ubiquitous modules
that have roles in other cellular processes in addition
to their role in the circadian system.