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                       BIOINFORMATICS COLLOQUIUM
                    School of Computational Sciences
                        George Mason University
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                Y-family DNA Polymerases and their Roles
                   in Mutagenesis and Carcinogenesis

                             Roger Woodgate
               Laboratory of Genomic Integrity, NICHD/NIH

                       Tuesday, October 21, 2003
                                4:30 pm
               Verizon Auditorium, Prince William Campus


Like many organisms, our genome is constantly subjected to DNA
damage. Despite a plethora of repair pathways to remove the damage,
lesions often persist which block basic cellular processes like
replication and transcription.  Recent studies suggest that cells
often circumvent these blocks by utilizing specialized DNA polymerases
that are able to replicate through the damaged DNA.  Many of these
polymerases are phylogenetically related and belong to the
UmuC/DinB/Rev1/Rad30 or Y-family of DNA polymerases.  The important
role that these polymerases play in protecting us from the deleterious
consequences of DNA damage is highlighted by the fact that defects in
human DNA polymerase-e lead to the sunlight-sensitive, cancer-prone
Xeroderma Pigmentosum Variant syndrome.  In addition to pol-e, humans
possess three other Y-family polymerases; Rev1, pol-k, and pol-i,
whose biological functions are presently unknown.

Y-family polymerases are ubiquitous and are found in all kingdoms of
life.  Of particular interest to us, is DNA polymerase IV (Dpo4), a
DinB homolog from the archaeon Sulfolobus solfataricus P2.
Characterization of Dpo4 reveals that the polymerase possesses
biochemical properties similar to eukaryotic members of the Y-family
including a propensity to bypass certain DNA lesions like a
thymine-thymine cyclobutane pyrimidine dimer (CPD).  S. solfataricus
Dpo4 has recently been crystallized and ternary complexes of the
polymerase together with a CPD and an incoming nucleotide have been
solved by X-ray crystallography.  These structures reveal that the
active site of the polymerase is sufficiently large enough to
accommodate the covalently linked pyrimidine dimer and the structural
studies provide a model as to how eukaryotic polymerases, like pol-e,
can efficiently and accurately bypass CPDs.


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