Research | O'Brien Lab
Explore Projects and Publications
PROJECTS
We collaborate in multidisciplinary teams to tackle a wide range of biochemical, biological and translational questions focused on DNA-protein interactions. Examples of several current and recent projects are described below.
DNA Ligase I in disorders of the immune system
Biallelic hypomorphic variants of human LIG1 cause a distinct primary immunodeficiency and our work has revealed a common theme of reduced catalytic activity and altered affinity for the magnesium ion cofactor. For this project we have collaborated with Dr. Scott Williams (NIEHS) and Dr. Charlotte Cunningham-Rundles (Mount Sinai School of Medicine).
DNA searching mechanisms
How do proteins solve the needle-in-the-haystack problem of continuously searching every one of our cellular genome’s ~12 billion nucleotides? We have developed biochemical and biophysical assays to probe the mechanisms used by DNA repair proteins to diffuse on DNA and locate damaged sites among the great excess of undamaged sites.
Nucleotide flipping by enzymes
Many DNA repair and DNA modifying enzymes use nucleotide flipping to rotate target sites 180 degrees out of the DNA duplex. We have developed rapid mixing spectroscopic approaches to study how flipping contributes to target recognition and catalysis by such enzymes.
Recent Publications
Fidelity of DNA Ligase I is sensitive to physiological Mg2+ level.
Beier DH, Lee E, Seong IS, Wheeler VC, O'Brien PJ.
J Biol Chem. 2026 Mar 25; 302 (5): 111407. DOI: 10.1016/j.jbc.2026.111407
PMID: 41895445
Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion.
Lee E, Kim W, Beier DH, Lee Y, Kovalenko M, Saif F, Oliver E, Srinageshwar B, Murtha R, Andrew MA, Jiang A, Gillis T, Demelo B, Ruliera J, Lucente D, Kwak S, Lee R, Pinto RM, MacDonald ME, Gusella JF, O'Brien PJ, Wheeler VC, Seong IS.
Proc Natl Acad Sci U S A. 2026 Mar 10; 123 (10): e2518854123. DOI:10.1073/pnas.2518854123
PMID: 41770933
Molecular basis for RNA discrimination by human DNA ligase 1.
Tumbale PP, Jurkiw TJ, Krahn JM, Bokil NV, Admiraal SJ, Pedersen LC, Williams JS, Kunkel TA, O'Brien PJ, Williams RS.
Nucleic Acids Res. 2025 Apr 10; 53 (7): gkaf299. DOI:10.1093/nar/gkaf299
PMID: 40239996
Rare variants of DNA ligase 1 show distinct mechanisms of deficiency.
Veenstra JH, Chabez A, Haanen TJ, Keranen A, Cunningham-Rundles C, O'Brien PJ.
J Biol Chem. 2024 Nov 5; 300 (12): 107957. DOI:10.1016/j.jbc.2024.107957
PMID: 39510190
Human DNA ligases I and III have stand-alone end-joining capability, but differ in ligation efficiency and specificity.
McNally JR, Ames AM, Admiraal SJ, O'Brien PJ.
Nucleic Acids Res. 2023 Jan 25; 51 (2): 796 - 805. DOI:10.1093/nar/gkac1263
PMID: 36625284
Genetic and chemotherapeutic influences on germline hypermutation.
Kaplanis J, Ide B, Sanghvi R, Neville M, Danecek P, Coorens T, Prigmore E, Short P, Gallone G, McRae J, Genomics England Research Consortium, Carmichael J, Barnicoat A, Firth H, O'Brien P, Rahbari R, Hurles M.
Nature. 2022 May; 605 (7910): 503 - 508. DOI:10.1038/s41586-022-04712-2
PMID: 35545669
LIG1 syndrome mutations remodel a cooperative network of ligand binding interactions to compromise ligation efficiency.
Jurkiw TJ, Tumbale PP, Schellenberg MJ, Cunningham-Rundles C, Williams RS, O'Brien PJ.
Nucleic Acids Res. 2021 Feb 22; 49 (3): 1619 - 1630. DOI:10.1093/nar/gkaa1297
PMID: 33444456
