Molecular Recognition of DNA Damage Sites by Apurinic/Apyrimidinic Endonucleases Page: 4 of 12
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Background and Significance
Genomic cloning has revealed that most of the enzyme families essential for maintaining cell growth
have been conserved throughout evolution. However, mammalian enzymes with different functional activity,
may have evolved by combining elements from several bacterial ancestral genes. Even small proteins may
contain several individual domains that link them to different superfamilies. While many endonucleases
share a common active site that is highly conserved across many subfamilies, identifying residues that
control substrate specificity requires sophisticated analysis that combines both sequence conservation and
In our project we developed a word-based "molego" approach, to identify structural elements that
control substrate specificity[2, 6]. We hypothesize that elements conserved in all the members of related
protein families dictate common structures and also common "functions", i.e., individual steps in a complex
reaction. Areas that affect substrate specificity will be less conserved in the superfamily than they are in
subfamilies of enzymes that catalyze specific activities. To provide the computational tools for this
approach, we developed a novel method, PCPMer, to automatically detect sequence motifs defined in terms
of the conserved physical-chemical properties (PCP) of residues in protein families .
We demonstrated the usefulness of our approach for the multifunctional family of DNA repair proteins,
the apurinic/apyrimidinic endonucleases (APEs), which have a clearly defined bacterial ancestor, E. coli
exonuclease III (ExolII), and several enzymes that are distantly related in activity and structure. APEI is a
multifunctional protein which was shown to be essential in an early mouse embryogenesis [8-10]. Because
of its multifunctional property, it has been difficult to assess the importance of the DNA repair function, until
two independent reports provided this year solid evidences that its DNA repair activity is pivotal to cells [5,
11]. Moreover, recent reports indicated that high levels of the APEl activity in tumor tissues correlated with
chemo- and radio-resistance of these tumors in adjuvant therapies [12, 13]. Structural/functional analyses of
the APE activity has thus been an important research field to solve such broader issues as to seek novel
approaches in cancer therapy, and to assess cellular defense mechanisms against ionizing radiation.
The PCPMer method.
We developed a novel method to automatically detect sequence motifs defined in terms of the conserved
physical-chemical properties (PCP) of residues in protein families. Conservation of physical-chemical
properties of amino acids in protein families is calculated from variation of five quantitative descriptors, El
to E5, (PCP-vectors) . These descriptors can reproduce the distances in the original property space with a
correlation coefficient of 99%. A sequence motif for a protein family is defined as contiguous segments that
are conserved in their PCP vectors. Each motif is quantitatively expressed as a physical-chemical property
profile (PCP-profile) that includes the average values of the PCP-vectors and their standard deviations. The
relative entropy of the actual distribution of PCP values and the 'a priori' distributions measures the statistical
significance of the conservation.
This methodology has been implemented in the PCPMer program, which generates PCP-motifs
automatically from sequence alignments. Computational tests have indicated that the method efficiently finds
homologous proteins in protein databases and common motifs in distantly related proteins. A patent
"Physical-chemical property based sequence motifs and methods regarding same" (U.S Patent application
serial No. 10/817,530, inventors: W. Braun, V. Mathura, C.H. Schein) for our method is pending.
PI: Braun, W.
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Braun, W. A. Molecular Recognition of DNA Damage Sites by Apurinic/Apyrimidinic Endonucleases, report, July 28, 2005; United States. (digital.library.unt.edu/ark:/67531/metadc874637/m1/4/: accessed September 24, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.