Williams Lab News

April 2024 – Northeastern physicists and National Cancer Institute researchers suggest that mechanical pressure triggers a key event in HIV infection

What triggers HIV-1 capsid uncoating? In @ScienceAdvances, with the Pathak lab at NCI, we show long dsDNA from reverse transcription is required for uncoating, likely due to mechanical pressure regulated by the nucleocapsid protein. The paper is here, and the Northeastern Global News story is here.

August 2023 – NIH – Chromatin modifications that enhance DNA accessibility

The Williams lab received a $2M grant from the National Institute of General Medical Sciences at NIH. The funding will allow the laboratory to study the molecular mechanisms that govern access to genomic DNA in human cells. Eukaryotic DNA is tightly packaged into nucleosomes, which form structural barriers to transcription, yet RNA polymerases effectively read through chromatinized DNA in cells. Crucial to this apparent paradox are ATP-independent histone chaperones, which include the heterodimeric FACT (FAcilitates Chromatin Transcription) complex and the monomeric proteins lens epithelium-derived growth factor (LEDGF) and hepatoma-derived growth factor 2 (HDGF2). Whereas FACT’s role as a histone chaperone is well-established, LEDGF and HDGF2 were only recently implicated as having histone chaperone activity. The proposed studies will probe the roles of these histone chaperones in controlling access to packaged genomic DNA.

May 2022 – NIH – Novel roles of viral proteins and host restriction factors in early HIV-1 replication events

The Williams lab received a $600K grant from the National Institute of Allergy and Infectious Diseases. The funding will allow the laboratory to investigate early-stage HIV-1 replication processes. HIV-1 integrates its genome into infected host cells. Due to the permanence of the integrated genome, it is advantageous to target HIV-1 replication in early stages, before integration. To rationally design new inhibitors of these early replication steps, a detailed molecular understanding is required. This work proposes integrated biochemical, biophysical, and cellular approaches to probe critical steps in early viral replication.

February 2020 – Professor Williams featured as part of the LUMICKS Dynamic Single-Molecule Symposium Series

The single molecule research from the Williams Lab was features as a keynote video presentation in the 8-part Lumicks Dynamic Single-Molecule Symposium Series. See the entire series here: https://t.co/r8gJJe0YV4?amp=1. Watch the Williams Lab video here:

August 2019 – The 11th International Retroviral Nucleocapsid and Assembly Symposium

Northeastern hosted the 11th International Retroviral Nucleocapsid and Assembly Symposium, August 15-17, 2019. The symposium provided a venue for ~80 researchers (principal investigators, postdoctoral fellows, students, research staff and representatives from biotechnology) to make progress in efforts to combat HIV-1/AIDS, as well as other retroviral diseases.

January 2019 – Unraveling the mysteries hidden in DNA

Principal Research Scientist Micah McCauley and graduate student Ran Huo published a paper in Nucleic Acids Research describing how HMGB proteins faciliate access to packaged DNA. See full Northeastern College of Science story here.

October 2018 – $1.1 M NSF Major Research Instrument grant received

Professor Williams and colleagues have received a $1.1 M NSF MRI grant to purchase a Lumicks SuperC-TRAP correlative optical tweezers and fluorescence microscope system. The CTFM instrument will allow users to measure and apply tension to single biomolecules with sub-picoNewton resolution, and to detect the presence, number, and position of individual fluorescently labeled molecules during these measurements in real time. This allows users to push or pull on biological systems and observe the reaction of the systems to force by using fluorescent labels. Simultaneously, the users can “feel” the reaction of the systems to these inputs through measurements of force or extension changes as the system responds to these inputs. Importantly, these observations reveal interactions at very small length scales, revealing activities of single proteins interacting with a substrate. Innovative projects at the forefront of interdisciplinary science will be enabled by this instrument, including projects to study how cellular DNA replication and repair of DNA damage occurs, how retroviruses copy their genomes, and how DNA is packaged (and can be unpackaged) in cells. Studies on collagen will probe how force affects tissue repair, while studies on polymer dynamics will use force to observe and direct protein assembly. The results of these studies will allow observation of real-time biological dynamics at the single molecule level, providing significant new insights into the functions of the biological systems probed.

August 2018 – NSF: Quantifying Single Molecule DNA-ligand Interactions

The Williams Lab has received a $900K grant from the National Science Foundation to continue studies of single molecule DNA interactions. This project uses DNA stretching with optical tweezers to probe biologically important molecular-level nucleic acid interactions that are particularly well-suited to probe with single molecule methods. Small molecule-DNA interactions will be studied, particularly for cases in which significant DNA structural rearrangements are required for DNA binding and dissociation. The properties of these small molecules that determine the DNA unfolding landscape will be measured, revealing critical information needed for the design of useful new ligands. LINE1 is a retrotransposon that is active in human cells. Recent studies probed the interaction between an essential LINE1-encoded protein, ORF1p, with nucleic acid, showing that its universally conserved coiled coil motif facilitates ORF1p oligomerization on nucleic acid. This project will probe the biophysical mechanism responsible for oligomerization, a process that is essential for retrotransposition. Finally, the activity of several E. coli DNA polymerases and polymerase manager or accessory proteins will be studied. These studies will reveal detailed interactions that are part of the bacterial response to DNA damage, a response essential for all life. This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.

October 2017 – One if by editing, two if by roadblock: Human protein fights HIV as monomer and dimer

Williams Lab postdoc Mike Morse and graduate student Ran Huo published a paper in Nature Communications describing APOBEC3G, a human innate immunity protein that is a cellular weapon in the battle with HIV-1 and retrotransposons.

See full Northeastern College of Science story here and the press release here.

December 2016 – Northeastern College of Science interview with Professor Williams

Mark Williams, Professor, Department of Physics

We sat down with Dr. Mark Williams, Professor in the Department of Physics, and learned about how molecules, such as DNA, work and interact. Read the full interview here

June 2015 – Williams lab awarded $1.5M NIH grant to continue studies on HIV-1 replication interactions

The objective of the funded work is to investigate the role of the HIV-1 nucleocapsid (NC) and reverse transcriptase (RT) proteins, as well as human APOBEC3 viral restriction factors, in the regulation of reverse transcription in retroviral systems. The proposed work combines single molecule methods with biochemical methods and measurements in cells to obtain a complete understanding of nucleic acid interactions involved in retroviral replication. We use these methods to probe the mechanisms by which retroviral proteins dynamically restructure and organize nucleic acids to facilitate replication, and to determine how these processes are regulated. To do this, the Williams Lab has pioneered single molecule nucleic acid stretching methods that quantitatively probe nucleic acid structural rearrangements and protein-nucleic acid interactions. In the previous cycle, we demonstrated that the capability of NCs to rearrange nucleic acids, referred to as nucleic acid chaperone activity, is directly correlated with HIV-1 replication in cells. The proposed work seeks to understand how this chaperone activity targets specific structures and facilitates nucleic acid reorganization without interfering with reverse transcription. In contrast to NC’s facilitation of reverse transcription, human APOBEC3 proteins may inhibit reverse transcriptase activity. We plan to probe the DNA interactions of several APOBEC3 proteins and directly monitor RT activity in the presence of APOBEC3 proteins as well as NC. The award amount is over $1.5M total for four additional years of research.