Patrick O'Brien, Ph.D.

Associate Professor, Biological Chemistry

4220B MSRB3, Box 5606

(734) 647-5821


Biological Chemistry, Medical School

Areas of Interest

DNA is remarkably stable, but nonetheless suffers a wide variety of spontaneous damage. Thus, it comes as no surprise that a substantial portion of the proteome is dedicated to maintaining and repairing DNA. Work over the past several decades has identified different types of DNA damage and developed a broad picture of many different pathways for DNA repair. This work sets the foundation for understanding the biochemical and biophysical mechanisms by which DNA damage is detected and ultimately repaired. These studies will expand our understanding of carcinogenesis and the ways in which our cells safeguard against it, and culminate in a more comprehensive view of the dynamic nature of chromosomal DNA.

DNA bases are readily oxidized and alkylated in vivo and the resulting lesions are usually repaired by base excision repair (BER). The BER pathway is an excellent model system for DNA repair, because it can be reconstituted in vitro with as few as four enzymes: DNA glycosylases survey the genome and initiate repair by excising damaged bases; an abasic site-specific nuclease subsequently creates a single-stranded nick and removes the deoxyribosyl group; finally, a polymerase and a ligase act in turn to restore the DNA.

We seek to understand the biochemical and biophysical principles by which DNA is repaired, starting with relatively simple repair pathways such as BER. For all DNA repair pathways we are interested in specificity (distinguishing damaged and normal DNA) and fidelity (how efficiently the damage is repaired). The physical principles and mechanisms by which specificity and fidelity are conferred are best addressed by mechanistic analysis in vitro. Ultimately, the chemical and physical principles governing the action of BER enzymes will be more broadly applicable to other DNA repair processes, and to other DNA-templated activities such as replication. For example, the processes of locating rare sites and coordinating multi-step, multi-component pathways have features common to most DNA-templated activities. By focusing on the human proteins we hope to speed the process by which mechanistic insight leads to practical applications, such as the improvement of anticancer chemotherapies, protection from environmental carcinogens, and the development of novel antimicrobials.

Laboratory Members

Suzanne Admiraal, Research Lab Specialist

 (734) 647-5827

Michael Baldwin, Research Lab Technician

(734) 647-5827

Tom Jurkiw, Graduate Student

(734) 647-5827

Justin McNally, Graduate Student

(734) 647-5827

Adam Thelen, Graduate Student

(734) 647-5827

Honors & Awards

1995-1997    NIH Biotechnology Predoc Fellowship
2002-2004    Ruth L. Kirchstein NRSA (NIH Postdoc fellowship)
2011-2015    Research Scholar of the American Cancer Society
2016             Basic Sciences Teaching Award, University of Michigan Medical School

Published Articles or Reviews

Taylor, E.L., Kesavan, P.M., Wolfe, A.E., & O'Brien, P.J. (2018) Distinguishing specific and nonspecific complexes of alkyladenine DNA glycosylase. Biochemistry 57: 4440-4454.
McNally, J.R. & O’Brien, P.J. (2017) Kinetic analyses of single-strand break repair by human DNA ligase III isoforms reveals biochemical differences from DNA ligase I. J. Biol. Chem. 292: 15870-15879.
Hendershot, J.M. & O’Brien, P.J. (2017) Search for DNA Damage by Human Alkyladenine DNA Glycosylase Involves Early Intercalation by an Aromatic Residue. J. Biol. Chem. 292:16070-16080.

Admiraal, S.J. & O’Brien, P.J. (2017) Reactivity and cross-linking of 5'-terminal abasic sites within DNA. Chem Res Toxicology 30:1317-1326.

Eyler, D., Burnham, K.A., Wilson, T.E., & O’Brien, P.J. (2017) Mechanisms of glycosylase induced genomic instability. PloS ONE 12:e0174041.

Zhang, Y. & O’Brien, P.J. (2015) Protection against alkylation damage depends on the searching ability of alkyladenine DNA glycosylase. ACS Chemical Biology 10:2606-15.

Admiraal, S.J., O’Brien P.J. (2015) Base excision repair enzymes protect abasic sites in duplex DNA from interstrand cross-links. Biochemistry 54:1849-57.

Taylor, E.L. & O’Brien, P.J. (2014) Kinetic mechanism for the flipping and excision of 1,N6-ethenoadenine by AlkA. Biochemistry, Epub Jan 14, 2015

 Zhang, Y., Hedglin, M., O’Brien, P.J. (2014) Probing the DNA structural requirements for facilitated diffusion. Biochemistry, Epub Dec 24, 2014

 Hendershot, J. & O’Brien, P.J. (2014)Critical role of DNA intercalation in enzyme-catalyzed nucleotide flipping. Nuc. Acids. Res. 42:12681-90. PMCID: PMC4227769

Hedglin, M., Zhang, Y., & O'Brien, P.J. (2013) Isolating contributions from intersegmental transfer to DNA searching by alkyladenine DNA glycosylase. J. Biol. Chem, epub

Admiraal, S.J. & O'Brien, P.J. (2013) DNA-N-glycosylases process novel O-glycosidic sites in DNA. Biochemistry, epub

Baldwin, M.R. & O'Brien, P.J. (2012) Defining the functional footprint for recognition and repair of deaminated DNA. Nucleic Acids Res., 40, 11638-47.

Taylor, M.R., Conrad, J.A., Wahl, D.R., & O'Brien, P.J. (2011) Kinetic mechanism of human DNA ligase I reveals magnesium-dependent changes in the rate-limiting step that compromise ligation efficiency. J. Biol. Chem., 286, 23054-62.

Zhao, B. & O'Brien, P.J. (2011) Kinetic mechanism for the excision of hypoxanthine by Escherichia coli AlkA and evidence for binding to DNA ends. Biochemistry, 50, 4350-9.

Hendershot, J.M., Wolfe, A.E., & O'Brien, P.J. (2011) Substitution of active site tyrosines with tryptophan alters the free energy for nucleotide flipping by human alkyladenine DNA glycosylase. Biochemistry, 50, 1864-74.

Admiraal, S.J. & O'Brien, P.J. (2010) N-glycosyl bond formation catalyzed by human alkyladenine DNA glycosylase. Biochemistry, 49, 9024-6.

Baldwin, M.R. & O'Brien, P.J. (2010) Coordination of the initial steps of human base excision repair via nonspecific DNA binding interactions. Biochemistry, 49, 7879-91.

Lyons, D.M. & O'Brien, P.J. (2010) Human base excision repair creates a bias toward -1 frameshift mutations. J. Biol. Chem., 285, 25203-12.

Hedglin, M. & O'Brien, P.J. (2010) Hopping enables a DNA repair glycosylase to efficiently search both strands and bypass a bound protein. ACS Chem. Biol., 5, 427-36.

Lyons, D.M. & O'Brien, P.J. (2009) Efficient recognition of an unpaired lesion by a DNA repair glycosylase. J. Am. Chem. Soc., 131, 17742-3.

Wolfe, A.E. & O'Brien, P.J. (2009) Kinetic mechanism for alkyladenine DNA glycosylase-catalyzed flipping and excision of 1,N6-ethenoadenine. Biochemistry, 48, 11357-11369.

Baldwin, M.R. & O'Brien, P.J. (2009) Human AP endonuclease stimulates multiple-turnover base excision by alkyladenine DNA glycosylase. Biochemistry, 48, 6022-33.

Hedglin, M. & O'Brien, P.J. (2008) Human alkyladenine DNA glycosylase employs a processive search for DNA damage. Biochemistry, 47, 11434-11445.

O'Brien, P.J. (2006) Catalytic promiscuity and the divergent evolution of DNA repair enzymes. Chem Rev. 106, 720-52.

Pascal, J.M., O'Brien, P.J., Tomkinson, A.E. and Ellenberger, T. (2004). Human DNA ligase I completely encircles and partially unwinds nicked DNA. Nature, 432, 473-478.

O’Brien, P.J. & Ellenberger, T. (2004). The Escherichia coli 3-methyladenine DNA glycosylase has a remarkably versatile active site. J. Biol. Chem., 279, 26876-26884.

O’Brien, P.J. & Ellenberger, T. (2004). Dissecting the broad substrate specificity of human 3-methyladenine DNA glycosylase. J. Biol. Chem. 279, 9750-9757.

O'Brien, P.J. & Ellenberger, T. (2003) Human alkyladenine DNA glycosylase uses acid-base catalysis for selective excision of damaged purines. Biochemistry. 42, 12418-12429.

For a complete list of this person’s PubMed publications, click HERE

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