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Alexander C. Drohat, PhD

Academic Title:


Primary Appointment:

Biochemistry and Molecular Biology


108 N. Greene St., 419

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Education and Training

I received a PhD in Biochemistry and Molecular Biology at the University of Maryland School of Medicine and completed postdoctoral training at the Johns Hopkins University School of Medicine and the University of Maryland Center for Advanced Research in Biotechnology (CARB; currently known as IBBR). I joined the Department of Biochemistry and Molecular Biology at the University of Maryland School of Medicine in 2005. Our research has been supported continuously by grants from the NIH since 2005.


Our research centers on two areas, DNA repair and epigenetic regulation. The nucleobases of DNA are amenable to a broad range of chemical alterations, a feature that enables enzyme-mediated modifications but also allows for threatening DNA damage. We study enzymes that find and repair DNA lesions, thereby maintaining genomic integrity and protecting against cancer and other diseases. We also investigate enzymes that perform essential functions in epigenetic regulation, by acting on modified DNA bases. We use a broad range of biochemical, biophysical, structural, and molecular approaches, and collaborate with many other research groups. Some of our current research interests are summarized below.

Highlighted Publications

A complete list of my publications is available at PubMedLinks to recent papers are provided in Research Interersts below.

Check out our review articles on DNA Repair and BER in epigenetics: 

Coey and Drohat (2016) Chem Rev

Bellacosa and Drohat (2015) DNA Repair

Drohat and Maiti (2014) Org Biomol Chem

Research Interests

DNA Repair – Avoiding mutations caused by mC deamination

Often termed the “5th base” in DNA, 5-methylcytosine (mC) is a key epigenetic mark in eukaryotes, and it functions in restriction modification systems of archaea and bacteria. However, mC also threatens genetic and epigenetic integrity. Deamination of mC to T generates G/T mispairs, and, upon replication, CàT transitions. Through this process, mC deamination causes many point mutations in cancer and genetic disease. Two human glycosylases remove T from G/T mispairs, TDG (thymine DNA glycosylase) and MBD4 (methyl binding domain IV). Like other glycosylases, they flip a damaged base into their active site and cleave the base-sugar bond; follow-on base excision repair (BER) enzymes complete the repair process. While most glycosylases excise bases that are foreign to DNA (e.g., uracil), these mismatch enzymes remove a canonical base, thymine, from rare G/T mispairs but not from the vast background of A:T pairs. Because aberrant action on A:T pairs can be mutagenic and cytotoxic, specificity is critical for these enzymes, and we are studying how it is attained. We also study how TDG and MBD4 recognize other damaged bases, including uracil and 5-fluorouracil (5FU), among others. TDG excision of 5FU contributes to the antitumor effects of 5FU, which is used to treat cancer.

Coey et al (2016) Nucleic Acids Res

Malik et al (2015) Nucleic Acids Res
Maiti et al. (2012) Proc Natl Acad Sci
Manvilla et al. (2012) J Mol Biol
Morgan et al. (2011) Nucleic Acids Res

Epigenetic Regulation - Base Excision Repair in active DNA Demethylation

Methyltransferases are known to convert C to mC, but the process for reversing this epigenetic modification had remained unclear. One mechanism involves DNA replication without subsequent remethylation. Recent studies establish a pathway for active DNA demethylation, involving TET (ten-eleven translocation) enzymes and TDG-initiated BER (Fig. 1). TET enzymes catalyze stepwise oxidation of mC, to give 5-hydroxymethyl-C (hmC), then 5-formyl-C (fC), and 5-carboxyl-C (caC). TDG excises fC and caC, and subsequent BER steps restore cytosine. This central function in epigenetic regulation likely explains findings that TDG is essential for embryonic development. We study the role of TDG and other BER enzymes in active DNA demethylation.

Maiti et al (2013) J Am Chem Soc

Maiti and Drohat (2011) J Biol Chem

Protein Regulation by SUMO binding and SUMO conjugation

TDG can be covalently modified by SUMO (small ubiquitin-like modifier) proteins, and it also features a SUMO interacting motif (SIM) that binds non-covalentlyto SUMO domains. The SIM can bind free SUMO, a SUMO domain that is tethered to another protein, and intramolecularSUMO (tethered to TDG). We are investigating the effect of SUMO binding and SUMO conjugation on TDG function(s), and testing the current paradigm that SUMO modification of product-bound TDG is needed to relieve product inhibition and allow for efficient catalytic turnover. We are also studying how SUMO modification of TDG is regulated in cells.

Coey at al. (2014) J Biol Chem
Fitzgerald and Drohat (2008) J Biol Chem