Molecular Recognition of DNA Damage Sites by Apurinic/Apyrimidinic Endonucleases Page: 1 of 12
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"Molecular recognition of DNA damage sites by apurinic/apyrimidinic
Final report, July 2005
Project period: 9/1/2000-11/30/2004
Werner A. Braun, Ph.D.
Dept. Human Biological Chemistry and Genetics, Sealy Center for Structural Biology
University of Texas Medical Branch, Galveston, TX 77555-1157
Phone: (409) 747-6810; FAX: (409) 747-4289; E-mail: firstname.lastname@example.org
The DNA repair/redox factor AP endonuclease 1 (APE1) is a multifunctional protein which is known to
to be essential for DNA repair activity in human cells. Structural/functional analyses of the APE activity is
thus been an important research field to assess cellular defense mechanisms against ionizing radiation.
We have taken a computational and experimental approach to elucidate the roles of residues in the
apurinic/apyrimidinic endonuclease 1 (APE1) that mediate interactions with damaged DNA and other
enzymes in the base excision repair (BER) pathway. During the project period, 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. This methodology
has been applied to the endonuclease superfamily and to DNase I related
nucleases/phosphatases to identify common sequence motifs important for metal binding and
catalytic activity[ 1-3].
" performed comprehensive molecular mechanics and dynamics calculations to investigate the
role of the metal ion in the catalytic process. These data support a novel mechanism for
cleavage of abasic sites in DNA by APE 1, in which the metal ion moves from a stable position
on the enzyme surface to a more solvent exposed one during DNA cleavage, aided in part by
ligands from the substrate (ins in preparation).
" Generated several mutants of APEl and performed biochemical analysis to identify amino acid
side chains important for substrate/product DNA binding and to analyze the nuclear transport
mechanism of APEI. In addition, we have created various APEI mutant cDNA and
recombinant proteins during this DOE project, including: (a) Cys to Ser missense mutants, (b)
insertion mutants that carry Xth signature inferred for its high exonuclease activity[4, 5].
" Applied for 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 PCPMer method. This methodology has been implemented in the PCPMer
program. The motif identification method is generally available to the scientific community via
our WEB server MASIA (http://www.scsb.utmb.edu/masia/masia.html). A standalone version
of the PCPMer program for motif generation and data base mining is available from our
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/m1/1/: accessed November 18, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.