Mark Hedglin
Professional Appointments and Affiliations
Huck Institute of the Life Sciences
Assistant Professor of Biochemistry and Molecular Biology
College of Medicine
Office
210A Wartik Lab
University Park, PA 16802
Education
Ph.D., Chemical Biology, University of Michigan, 2010
B.A., Biochemistry, Ithaca College, 2005
Honors and Awards
NIH Ruth L. Kirschstein NRSA Postdoctoral Fellowship, 2012 – 2015
Research
The genetic information (i.e., genome) of a human cell is encoded in strands of DNA that assemble into an antiparallel DNA double helix. Each time a cell divides, the genome must be faithfully replicated and transferred to a daughter cell for genetic inheritance. The former occurs during S-phase of the cell cycle and relies on high-fidelity, i.e. “replicative,” DNA polymerases that read template DNA strands and synthesize their complementary DNA. Additional “core” proteins and enzymes are also involved and the basic mechanism of human DNA replication has been deciphered. However, it is currently unknown how DNA replication is achieved on genomic DNA within a human cell. For example, the majority of proteins and enzymes implicated in human DNA replication are dynamically modified by chemical and protein moieties in vivo. Currently, the functional role and regulation of many of these modifications is unknown. Furthermore, genomic DNA is continuously subjected to damage from reactive metabolites and environmental mutagens. Prominent examples are modifications (lesions) to the native template DNA bases that alter or eliminate their base pairing capability. It is unclear how DNA lesions are accommodated during S-phase without compromising the fidelity of DNA replication. We aspire to decipher how efficient and faithful replication of the human genome is achieved within the highly-complex, dynamic, and reactive cellular environment. To do so, we employ a multi-disciplinary, collaborative approach, combining biophysical, biochemical, and molecular and cellular biology techniques to; 1) identify cellular factors involved in various aspects of human DNA replication and; 2) re-constitute human DNA replication in various biological scenarios and at various levels of complexity.
Selected Publications
Hedglin, M., Aitha M., Pedley A., and Benkovic, S.J. Replication protein A dynamically regulates monoubiquitination of proliferating cell nuclear antigen. J Biol Chem. 2019 Mar 29; 294(13): 5157-5168.
Hedglin, M., Aitha M., and Benkovic, S.J. Monitoring the Retention of Human PCNA at Primer/Template junctions by Proteins that Bind Single-stranded DNA. Biochemistry, 2017, 56, 3415 – 3421.
Hedglin, M. and Benkovic, S.J. Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours Around the Same Obstacle. 2017, ACS Chemical Reviews, 117, 7857 – 7877.
Hedglin, M. and Benkovic, S.J. Replication protein A prohibits diffusion of the PCNA sliding clamp along single-stranded DNA. Biochemistry, 2017, 56, 1824 – 1835.
Hedglin, M., Pandey, B., and Benkovic, S.J. Characterization of human translesion DNA synthesis across a UV-induced DNA lesion. 2016, eLife 5, e19788.
Hedglin, M., Pandey, P., and Benkovic, S.J. Stability of the human polymerase δ holoenzyme and its implications in lagging strand DNA synthesis. 2016, Proc Natl Acad Sci U S A, 113, E1777 - E1786.
Hedglin, M., Zhang, Y., and O'Brien, P.J. Probing the DNA structural requirements for facilitated diffusion. Biochemistry, 2015,54, 557-566.
Hedglin, M., and Benkovic, S.J. Regulation of Rad6/Rad18 Activity During DNA Damage Tolerance. Annu Rev Biophys, 2015, 44, 207-228.
Hedglin, M., Zhang, Y., and O'Brien, P.J. Isolating contributions from intersegmental transfer to DNA searching by alkyladenine DNA glycosylase. J Biol Chem, 2013, 288, 24550-24559.
Hedglin, M., Perumal, S.K., Hu, Z., and Benkovic, S. Stepwise assembly of the human replicative polymerase holoenzyme. eLife, 2013, 2, e00278.
Hedglin, M., Kumar, R., and Benkovic, S.J. Replication clamps and clamp loaders. Cold Spring Harb Perspect Biol, 2013, 5, a010165.
Hedglin, M., and O'Brien, P.J. Hopping enables a DNA repair glycosylase to search both strands and bypass a bound protein. ACS Chem Biol, 2010, 5, 427-436.
Hedglin, M., and O'Brien, P.J. Human alkyladenine DNA glycosylase employs a processive search for DNA damage. Biochemistry, 2008, 47, 11434-11445.
Krennhrubec, K., Marshall, B.L., Hedglin, M., Verdin, E., and Ulrich, S.M. Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors. Bioorg Med Chem Lett, 2007, 17, 2874-2878.