Possible Rotation Projects:
Mechanistic studies of ATM kinase activation by the MRN complex
Regulation of DNA repair proteins at telomeres
Mechanisms of DNA resection regulation
Training Technologies Used:
- Protein purification and biochemical assays
- Single-molecule microscopy
- Cell line assays and microscopy
- Structure prediction and evolutionary biology
- BS, Biochemistry, The University of Texas at Austin, 2012
- PhD, Cell and Molecular Biology, The University of Texas at Austin, 2018
Sottnik JL, Shackleford MT, Nesiba CS, et al. Altered MDC1 Interactions and Dysfunctional DNA Repair in Lobular Breast Cancer Confers Sensitivity to PARP Inhibition. Cancer Res. Published online January 9, 2026. doi:10.1158/0008-5472.CAN-25-1217
Goldfarb AM, Sasi NK, Dilgen TC, Cai SW, Myler LR, Lange T de. Tetrameric TRF2 forms t-loop to protect telomeres from ATM signaling and cNHEJ. bioRxiv. Preprint posted online June 28, 2024:2024.06.27.600884. doi:10.1101/2024.06.27.600884
Soniat MM, Myler LR. Using the safety scissors: DNA resection regulation at DNA double-strand breaks and telomeres. DNA Repair. 2025;152:103876. doi:10.1016/j.dnarep.2025.103876
Kinzig CG, Zakusilo G, Takai KK, Myler LR, de Lange T. ATR blocks telomerase from converting DNA breaks into telomeres. Science. 2024;383(6684):763-770. doi:10.1126/science.adg3224
Myler LR, Toia B, Vaughan CK, et al. DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres. Nat Struct Mol Biol. 2023;30(9):1346-1356. doi:10.1038/s41594-023-01072-x
Myler LR, Kinzig CG, Sasi NK, Zakusilo G, Cai SW, de Lange T. The evolution of metazoan shelterin. Genes Dev. 2021;35(23-24):1625-1641. doi:10.1101/gad.348835.121
Deshpande RA, Myler LR, Soniat MM, et al. DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP. Sci Adv. 2020;6(2):eaay0922. doi:10.1126/sciadv.aay0922
Soniat MM, Myler LR, Kuo HC, Paull TT, Finkelstein IJ. RPA Phosphorylation Inhibits DNA Resection. Mol Cell. 2019;75(1):145-153.e5. doi:10.1016/j.molcel.2019.05.005
Myler LR, Gallardo IF, Soniat MM, et al. Single-Molecule Imaging Reveals How Mre11-Rad50-Nbs1 Initiates DNA Break Repair. Mol Cell. 2017;67(5):891-898.e4. doi:10.1016/j.molcel.2017.08.002
Myler LR, Gallardo IF, Zhou Y, et al. Single-molecule imaging reveals the mechanism of Exo1 regulation by single-stranded DNA binding proteins. Proc Natl Acad Sci U S A. 2016;113(9):E1170-1179. doi:10.1073/pnas.1516674113
DNA double-strand breaks are the most deleterious of DNA lesions and must be rapidly sensed and repaired to prevent genome instability. On the other hand, human chromosomes are linear and the ends resemble DNA breaks. Therefore, the cell must also prevent double-strand break repair machinery at the natural ends, or telomeres. My lab studies the basic mechanisms by which proteins recognize and repair double-strand breaks while preventing inappropriate processing at telomeres. We use a combination of single-molecule biophysics (C-Trap), structural biology and prediction (Cryo-EM and AlphaFold), biochemistry, and cell biology to discover the detailed actions of DNA repair and telomere maintenance proteins. In particular we’ve studied the Mre11-Rad50-Nbs1 complex (MRN), which recognizes DNA ends, activates the ATM kinase, and begins DNA resection with the help of CtIP. MRN slides on DNA to recognize even blocked DNA ends by a topological mechanism and then undergoes a large conformational change to enable its downstream activities. Understanding these basic mechanisms have profound implications for cancer biology and treatment since most cancer therapies cause DNA double-strand breaks (chemotherapy and radiation). In addition, new targeted therapies utilize differential DNA repair pathway choice in cancer to selectively kill cancer cells. Overall, these studies provide insight into basic mechanisms with the goal of understanding and treating both cancer and aging.
