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Manel Camps
Assistant Professor of Environmental Toxicology
D.V.M. Autonomous University of Barcelona (Doctor in Veterinary Medicine)
M.A. Autonomous University of Barcelona (Biochemistry)
Ph.D. Stanford University (Microbiology and Immunology)
Office: PSB
434, Office Hours: By
appointment
Email: mcamps@ucsc.edu
Office Phone: (831) 459-5396
Lab Phone: (831) 502-7197
Fax: (831) 459-3524
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Research Group: Camps Lab
Molecular mechanisms of reactive DNA methylation toxicity.
Employment
Opportunities: Postdoctoral
Scholar
Methylating
Agents and the Treatment of Cancer
Spontaneous DNA
Methylation results from methyl donors reacting
with DNA. DNA methylation is a potent carcinogen.
Paradoxically, in addition to being carcinogenic,
methylating agents are also mainstays for cancer
treatment. Among his research interests, Dr.
Camps examines the molecular mechanisms of
methylating agent toxicity to design safer and
more effective strategies for cancer
chemotherapy.
Methylation refers
to the replacement of a hydrogen atom with a
methyl group. DNA is a frequenttarget of
methylation. DNA methylation can occur
spontaneously or enzymatically. Spontaneous DNA
methylation is genotoxic, whereas enzymatic DNA
methylation is tolerated and a major mechanism of
epigenetic regulation of gene expression. Dr.
Campís research focuses on spontaneous DNA
methylation. Methyl group donors include
metabolic products present in a cell, or
exogenous agents such as antimicrobial compounds
segregated during inflammation, certain drugs,
and agents found in the environment (in food,
cigarette smoke or air pollution).
Methylating
Agents Can Both Induce and Kill
Cancer
Within the DNA,
methylation can affect any atom on the base ring
or phosphodiester bond. The frequency and
deleterious effect of each adduct, however,
varies depending on its specific location on the
base. Four adducts are considered to be mainly
responsible for the deleterious effects of
methylating agents based on their frequency and
toxicity. Three of these adducts, N3-meA,
N1-meA, and N3-meC, block the progression of the
replication fork. Another one, O6-meG, causes
mispairing. All four types of adducts are
cytotoxic. In addition, these lesions lead to
genetic instability and are therefore
carcinogenic.
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Interestingly, tumor
cells are very sensitive to methylating agent
toxicity. Thus, while being potent carcinogens
themselves, methylating agents can be used to
treat cancer. Unfortunately, treatment with
methylating agents, such as temozolomide, causes
bone marrow toxicity. This potentially
life-threatening side effect often limits the
dosage and duration of treatment with such drugs.
The Camps laboratory
studies the molecular mechanisms of methylation
toxicity. These studies can be used to improve
the design of more efficient strategies to kill
tumor cells, as well as to manage the side
effects caused by these chemotherapies.
The Molecular
Mechanisms of Methylating Agents
This promiscuity
of methytating agents, i.e. the fact
that they generate a variety of DNA adducts has
made the study of molecular mechanisms of
toxicity very difficult. Remarkably, the
cytotoxic lesions caused by N1-meA and N3-meC can
be specifically removed or “repaired”
without any adverse effects. This repair reaction
is enzymatic and mediated by a single gene
product, so there is a direct correlation between
the efficiency of repair of cytotoxic adducts by
the enzyme and cellular protection. Thus,
cellular protection can provide reliable
information on the biological effects of a
particular lesion. This mechanism of repair
also holds great potential for the protection of
bone marrow cells from methylation toxicity, as
it is error-free, enzymatic, and is mediated by a
single protein, which means that, by necessity,
it is the rate-limiting step.
 At present,
researchers in the Camps lab are modifying the
enzymatic activity of ABH2, the human gene that
mediates the repair reaction mentioned above, so
that it is able to repair other cytotoxic lesions
and thus confers improved cellular protection.
MNNG is a methylating agent that generates
abundant O6-meG and N3-meA. The Camps group has
already generated a library of human
ABH2-encoding random mutations and performed
complementation studies in E. coli to
select for mutants that confer increased MNNG
protection. Their goal is to find mutants that
are highly efficient at repairing O6-meG, 3-meA,
or both. With this in mind, Dr. Camps has
established a collaboration with Tomas Lindahl
and Barbara Sedgwick at the Cancer Research UK
London Research Institute to characterize the
substrate specificity of these mutants. As
a first critical step toward establishing the
translational potential of these mutants, Camps'
group will test the most promising candidate
mutants in human and mouse hematopoietic stem
cells. Ultimately, they hope to generate
transgenic mouse models that express mutant ABH2
genes to determine the biological effects of
individual DNA adducts, as well as establish if
these enhanced mutants increase bone marrow
protection.
ABH2 evolution
under MNNG selection, in addition to having
implications for understanding and managing
methylating agent toxicity, constitutes a model
of functional adaptation in the test tube.
Directed evolution experiments generate new
enzymatic activities in a short time and under
controlled conditions, thus providing information
about how new activities may evolve in nature. In
this case, selected ABH2 mutants will
provide information about how the substrate
specificity and/or the chemistry of a given
reaction can be modified with a few amino acid
changes. Such information has broad
evolutionary implications and should improve our
ability to customize enzymatic activity for
biomedical and biotechnological applications.
Selected
Publications
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M. Camps, A.
Herman, L. A. Loeb. 2007. Genetic Constraints on
Protein Evolution. Critical Reviews in
Biochemistry and Molecular Biology. 42:313-32. PDF -
T. T. Van,
S.-K. Kim, M. Camps, J. C. Boothroyd, L. J.
Knoll. 2007. The BSR4 protein is up-regulated in
Toxoplasma gondii bradyzoites, however the
dominant surface antigen recognised by the P36
monoclonal antibody is SRS9. International
Journal of Parasitogy 37:877-875. PDF -
M. Camps,
L.A. Loeb. 2005. Critical role of R-loops in
processing replication forks. Frontiers in
Bioscience. 10: 689-698. PDF -
M. Camps,
L.A. Loeb. 2004. When pol I goes into high gear:
processive DNA synthesis by pol I in the cell.
Cell cycle. 3:116-8. PDF -
M. Camps,
L.A. Loeb. 2003. Targeted mutagenesis in E. coli:
a powerful tool for the generation of random
mutant libraries. Discovery Medicine. 3:18,
36-37. PDF -
M. Camps, J.
Naukkarinen, B. Johnson, L. A. Loeb. 2003.
Targeted gene evolution in E. coli using a highly
error-prone DNA polymerase I. Proceedings of the
National Academy of Sciences of the United States
of America. 100:9727-32. PDF -
M. Camps, L.
A. Loeb. 2003. Use of Pol I-deficient E. coli for
functional complementation of DNA polymerase. IN:
Directed Evolution Library Creation: Methods and
Protocols, (eds., F.H. Arnold and G. Georgiou).
Methods in Molecular Biology. 230:11-18.
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M. Camps, G.
Arrizabalaga, J. C. Boothroyd. 2002. An rRNA
mutation identifies the apicoplast as the target
for clindamycin in Toxoplasma gondii.Molecular
Microbiology. 43:1309-1318. PDF -
M. Camps, J.
C. Boothroyd. 2001. Toxoplasma gondii: selective
killing of extracellular parasites by oxidation
using PDTC. Journal of Experimental Parasitology.
98:206-214. PDF -
D.C. McFadden,
M. Camps, J. C. Boothroyd. 2001. Resistance as a
tool in the study of old and new drug targets in
Toxoplasma. Drug Resistance Updates. 4:79-84. PDF
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F. Posas, M.
Camps, and J. Ariño. 1995. The PPZ protein
phosphatases are important determinants of salt
tolerance in yeast cells. Journal of Biological
Chemistry. 277:13036-13041. PDF
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