[ RadSafe ] Article: DNA repair mapped, systems-wide

[John Jacobus]

>From The Scientist 
at http://www.the-scientist.com/news/daily/23466/

As noted:
". . . The researchers found 30 transcription factors
that appeared to be involved in the damage response .
. ."

--------------------------
NEWS
DNA repair mapped, systems-wide
  
  By Melissa Lee Phillips 

Scientists use sweeping approach to generate map of
interconnected cellular responses to DNA damage

[Published 19th May 2006 06:13 PM GMT]
 
-------------------------------------------------------

 Many cellular processes -- including DNA replication
and repair, cell cycle control, metabolism, and stress
responses -- form an integrated response to DNA
damage, according to a report in this week's Science.
The authors used a systems biology approach to create
a map of transcriptional networks that are activated
when yeast DNA is damaged. 

"We now know an order of magnitude more pathway
connections than were known before, as far as how
information is transmitted through the cell in
response to damage," senior author Trey Ideker of the
University of California, San Diego, told The
Scientist. Looking at cellular processes from a
wide-angle view -- rather than the one-gene,
one-protein approach of classical biology -- permits
the construction of "a complete wiring diagram" of
transcriptional interactions, Ideker said, which will
help scientists control cellular response to DNA
damage. 

Scientists have gathered significant data about how
DNA damage is sensed and repaired in the cell, Ideker
explained, and previous work has shown that many
pathways other than classic "repair" pathways become
activated after damage. "What's been entirely unknown
is how those different pathways are interlinked to
form one cohesive response," Ideker said. 

Ideker and his colleagues -- led by Christopher T.
Workman and H. Craig Mak, also at UCSD -- first
screened yeast cells for transcription factors
involved in the cellular response to an alkylation
agent called methyl-methanesulfonate (MMS). The
researchers found 30 transcription factors that
appeared to be involved in the damage response --
either because their expression changed with MMS
treatment, they bound to promoters of genes whose
expression changed with MMS treatment, or their
deletion diminished a cell's ability to recover from
damage. 

The authors then used a technique called ChIP-chip --
chromatin immunoprecipitation combined with microarray
chip hybridization -- to identify the transcriptional
network that each of the 30 transcription factors
induces when exposed to MMS. By comparing the genes
and protein-DNA interactions after MMS treatment to
interactions under normal growth conditions, the
authors mapped how transcription factors change their
behavior when the cell experiences DNA damage. These
changes include employing different DNA binding
motifs, altering regulated genes, or changing pairings
with other transcription factors. 

Ideker and his colleagues next used microarrays of
yeast genetic knockouts to determine how deleting a
key transcription factor changes gene expression
induced by MMS. If the ChIP-chip analysis showed that
a transcription factor binds to promoters of a certain
set of genes, the authors reason, then knocking out
that transcription factor should alter those genes'
response to MMS treatment. Since transcription factors
can also affect genes that they don't bind directly,
however, the authors also applied a Bayesian modeling
technique to determine likely intermediate factors
through which transcription factors modulate
downstream gene activity. 

The resulting transcriptional network shows how
transcription factors regulate the expression of 82
genes in response to MMS damage. At the core of the
network lies a set of known DNA damage response genes,
but surrounding these genes are interacting networks
involved in DNA replication and repair, cell cycle
arrest, stress responses, and metabolic pathways.
"We've now explained all of these pathways that people
have hinted at before within the context of one
circuit diagram," Ideker said. 

"I really liked the concept of the paper," said
Yolanda Sanchez of Dartmouth Medical School in
Hanover, NH, who was not involved in the study. "They
took a lot of information that was already out
there... and figured out connections between the
pathways." 

In future studies, it will be important to add
analyses of post-transcriptional and
post-translational mechanisms to what they've revealed
about transcriptional pathways, Sanchez added. "I'm
sure that's coming." 

"They certainly uncovered some novel connections and
pathways that weren't known before," said Grant Brown
of the University of Toronto in Ontario. "The biology
is not followed up in any rigorous sense, but the
point of this is to generate novel ideas that then
lead to more hypothesis-driven experiments." 

Links within this article 

C.T. Workman et al., "A systems approach to mapping
DNA damage response pathways," Science, May 19, 2006. 
http://www.sciencemag.org 

M.B. Castan, "DNA damage responses: Cancer and
beyond," The Scientist, October 10, 2005. 
http://www.the-scientist.com/article/display/15766/ 

Trey Ideker 
http://chianti.ucsd.edu/idekerlab/index.html 

J.F. Wilson, "Elucidating the DNA damage pathway," The
Scientist, January 21, 2002. 
http://www.the-scientist.com/article/display/12816/ 

S.A. Jelinsky, L.D. Samson, "Global response of
Saccharomyces cerevisiae to an alkylating agent,"
PNAS, February 16, 1999. 
PM_ID: 9990050 

Yolanda Sanchez 
http://www.dartmouth.edu/~sanchezlab/ 

Grant Brown 
http://biochemistry.utoronto.ca/brown/ 


+++++++++++++++++++
"You get a lot more authority when the workforce doesn't think it's amateur hour on the top floor."
GEN. MICHAEL V. HAYDEN, President Bush's nominee for C.I.A. director.

-- John
John Jacobus, MS
Certified Health Physicist
e-mail:  crispy_bird at yahoo.com

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