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Biochemistry and Molecular Biotechnology Program

The Graduate Program in Biochemistry and Molecular Biotechnology offers graduate study and research focused in the areas of molecular, cellular and regulatory biochemistry, molecular biophysics, chemical biology, and structural biology.  Students receive a rigorous foundation in modern biomedical science through an integrated program of laboratory research, advanced coursework, and attendance and participation in seminar programs.  Students also organize and participate in a weekly informal seminar series in which they present recent research results.

Specific areas addressed within program laboratories include protein structure, function and evolution, regulation of gene expression, chromatin structure and epigenetics, translational regulation, membrane transport, ion channel function, drug resistance, cell cycle control, DNA replication, and neurodegenerative disease.

REQUIREMENTS FOR SPECIALIZATION

All Basic Biomedical Science students must complete the core curriculum as well as electives required by their program. Students in the Biochemistry and Molecular Biotechnology (BMB) program must take 3 graded elective courses of 2-4 credits each, two of which must be part of the BMB program course curriculum. The third elective is typically taken in Year 2; however, the student should enroll in a course (regardless of when it is offered) that is most relevant to their graduate research. The plan of coursework is designed to be flexible in order to accommodate each student’s needs and areas of interest.

All students in thesis research are required to give an annual research presentation to the Department in a seminar series that runs from September through May each academic year.

View PhD Program Schedule  |  View Courses

OUR LEADERSHIP & FACULY

PROGRAM DIRECTOR

Brian Kelch headshotBrian Kelch, PhD
Associate Professor
email Dr. Kelch  |  Learn more about the Kelch Lab

FACULTY

Our faculty include, Howard Hughes Medical Institute Investigators, W. M. Keck Foundation Distinguished Young Scholars, Burroughs Wellcome Fellows, Worcester Foundation for Biomedical Research Scholars, a Pew Scholar and a faculty member who patented discoveries in RNAi.

Research areas of our faculty include:

  • Biophysics
  • Chemical Biology
  • Computational Biology
  • Cell & Developmental Biology
  • DNA/RNA & Epigenetics
  • Human Disease & Therapeutics
  • Membrane Biology
  • Neurobiology
  • Structural Biology

View the affiliated faculty listing for the Biochemistry and Molecular Biotechnology Program.

OUR STUDENTS

The Graduate Program in Biochemistry and Molecular Biotechnology is an integral part of the Department of Biochemistry and Molecular Biotechnology.  Our graduate students are core members of our world-class research teams and a central part of our departmental culture.  Students organize our weekly departmental research seminar and happy hour, where they and other department members present their research.  They also present at our annual departmental research retreat, the university research retreat and at national and international meetings.  Many of our students are funded by NIH pre-doctoral fellowships and several have been awarded the prestigious Harold Weintraub award.

STUDENT SPOTLIGHT

Qiu Yu (Judy) Huang

Qiu Yu (Judy) Huang's thesis project uses cryo-electron tomography to study influenza viruses. 

Learn more about Judy Huang

Emily Agnello, PhD'23

As a student, Emily Agnello focused on investigating the features of a bacteriophage (phage), or a virus that infects bacteria. 

Learn more about Emily Agnello, PhD'23

Xingchen Liu, PhD'23

Xingchen Liu investigated the mechanism of protein complexes important for DNA replication and repair while a UMass Chan student.

Learn more about Xingchen Liu, PhD'23

EXTERNAL AWARDS FOR RESEARCH TRAINING (CURRENT)

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    Investigating the Activation Mechanism of SARM1 during Axon Degeneration

    After injury, axons begin to die via a process that is characterized by axonal fragmentation and disintegration of myelin sheath. This process is often termed Wallerian degeneration after Augustus Waller. Wallerian-like degeneration, which is morphologically similar to Wallerian degeneration, is associated with the early stages of many neurodegenerative diseases, including as Alzheimer’s, Huntington’s, and Parkinson’s Diseases. Wallerian degeneration was long thought to occur passively, but the discovery of proteins that actively prevent or promote degeneration negated this idea. One such protein is SARM1. SARM1 is a NAD+ hydrolase that cleaves NAD+ to nicotinamide, ADPR, and cyclic ADPR; generation of these products ultimately leads to axonal degeneration. Moreover, SARM1 knockout delays degeneration in animal models of Wallerian-like diseases, including traumatic brain injury and peripheral neuropathy. Given the critical role of SARM1 in Wallerian-like diseases, the central hypothesis of this proposal is that SARM1 inhibition would prevent the pathophysiology of axon degeneration associated with neurodegenerative diseases. However, development of SARM1 inhibitors is limited by the lack of knowledge surrounding the regulation, structure, and mechanism of this enzyme. As such, the goal of this proposal is to understand SARM1 regulation in the context of Wallerian degeneration, and this goal will be achieved by pursing the following Specific Aims. Aim 1 focuses on identifying proteins that regulate SARM1 activity. Proximity dependent labeling will also be used to identify proteins that interact with SARM1. The impact of SARM1 interacting proteins on NAD+ hydrolase activity and SARM1-mediated axon degeneration will also be assessed. These experiments will identify intermolecular events that regulate SARM1 during axon degeneration. Aim 2 will focus on understanding the structure and function of TIR-1, the C. elegans ortholog of SARM1. Here, we will solve the TIR-1 structure and characterize the enzymatic mechanism of this enzyme. These studies will complement recent structural and kinetic studies of SARM1 and will yield insights into the intramolecular characteristics of SARM1/TIR-1 that contribute to its degenerative capacity. Investigation into the regulation of SARM1, both inter- and intramolecularly, is a rapidly growing field in the context of neurodegenerative diseases. As such, completion of this work will significantly enhance our understanding of the fundamental molecular mechanisms that control axonal degeneration. These studies will yield insights into the role of SARM1 in axon degeneration, which will have broad implications in the development of therapeutics for neurodegenerative diseases.

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  • Joseph Magrino - Kelch Research Group - Funding provided by National Institues of Health

    Investigating sliding clamps and their contribution to genome stability

    All cells must replicate their genome once per cell cycle. To ensure proper duplication, cells integrate hundreds of factors that copy, surveil, and repair our genetic information. Proliferating Cell Nuclear Antigen [PCNA] and Rad9-Rad1-Hus1 [9-1-1] are ring-shaped clamps that act as master “conductors” that regulate many of the factors that replicate and maintain our DNA. PCNA is a homotrimeric ring that coordinates the replisome during DNA synthesis to work in tandem with DNA repair, chromatin remodeling, and cell cycle progression. When cells experience dsDNA breaks, they use the heterotrimeric clamp 9-1-1 to coordinate specific “SOS” repair factors. The collaborative efforts of both clamps are critical for genome stability. Many cancers are linked to inappropriate clamp coordination and changes in their expression. Because sliding clamps are central to many oncogenic pathways, we must address how they regulate themselves and their client partners. This proposal aims to address the following questions about sliding clamps: 1) How do sliding clamps coordinate their various partners? 2) Does the time sliding clamps spend on DNA influence genome stability? and 3) What determines site-specific loading of sliding clamps? I propose a multidisciplinary approach to address these questions about sliding clamps by investigating two-disease causing PCNA variants [PCNA-S228I [serine to isoleucine] and PCNA-C148S [cysteine to serine]] and the loading mechanism of 9-1-1. I hypothesize that sliding clamps control genome integrity via site-specific loading, proper partner interactions, and residence-time on DNA. I further hypothesize that PCNA-S228I and PCNA-C148S disrupt genome integrity by either promoting premature DNA dissociation or disrupting partner interactions. Finally, I hypothesize that the Rad17 subunit alters the clamp loader structure to specifically load the 9-1-1 clamp at sites of DNA damage. In aims 1 and 2, I will use PCNA-S228I and PCNA-C148S to address how clamps “choose” their partners and regulate their time on DNA. I will use x-ray crystallography, unfolding experiments, and a series of functional assays to determine how each variant compromises genome stability. In aim 3, I will determine the loading mechanism of clamp 9-1-1 to address how clamps are loaded to specific sites in the genome. I will use cryo-electron microscopy to determine how Rad17-RFC binds to clamp 9-1-1. Collectively, my work will broaden our insight into the factors that cause genome instability which may augment the development of personalized chemotherapeutics.

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EXTERNAL AWARDS FOR RESEARCH TRAINING (PAST)

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    Structure-based design of potent and selective chemically modified oligonucleotide inhibitors for APOBEC3 enzymes

    The apolipoprotein-B mRNA-editing catalytic polypeptide-like 3 (APOBEC3, or A3) family of cytosine deaminase enzymes forms part of the innate immune system - hypermutating cytosine (C) to uracil (U) in single-stranded DNA (ssDNA), as a first response to invading viruses. Specific A3 enzymes, including A3G, were first shown to potently restrict human immunodeficiency virus (HIV). However, expression of these enzymes is a delicate balance – low level deamination of the HIV genome provides a constant source of viral mutation, contributing to high viral fitness and rapid resistance to anti-viral drugs. Moreover, upregulation of other A3 enzymes, like A3A and A3B, is linked to many cancers, helping to expand genetic diversity in tumors to supercharge progression, metastasis, recurrence, and drug resistance. Abolishing activity of specific A3 enzymes may slow viral evolution and prevent tumor recurrence. Structural examination of A3 active sites reveal their close homology to that of human cytidine deaminase (CDA), which converts C to U in single nucleosides. Introducing CDA inhibitors (transition state analogues, or TSAs) in place of the target C in ssDNA enables delivery to the A3 active site. Yet, development of selective inhibitors against individual A3 family members remains a challenge. Recently, our lab solved the co-crystal structures for A3A-ssDNA and A3G-ssDNA, and have also discovered that both the tertiary structure and DNA sequence flanking the target cytosine confer specificity to different A3 enzymes. I hypothesize that by exploiting these preferences – through manipulation of DNA sequence, oligonucleotide tertiary structure, and rational placement of chemical modifications – I can create potent and selective A3 inhibitors. Leveraging the Watts lab’s expertise in nucleic acid chemistry and the Schiffer lab’s extensive experience with A3G, I will first develop A3G-selective inhibitors, and then A3A and A3B inhibitors.

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  • Emily Agnello, Kelch Lab, Funding provided by National Science Foundation

    Elucidating the structural and mechanistic features of a thermophilic bacteriophage

    As the most abundant and deadliest entities on earth, bacteriophage play an essential role in many biological environments. While there are well-developed phage model systems that have informed our understanding of phage in the past 60 years, these systems have structural limitations. Here, we use a unique thermophilic siphovirus, P74-26, with extraordinary strength and stability to fill in the knowledge gaps that remain and take a closer look at some of the fascinating abilities of a phage that developed under the evolutionary pressure of a hot spring. Double-stranded DNA (dsDNA) viruses, which include bacteriophage along with herpesviruses, adenoviruses, use a powerful ATPase motor to pump their genome into an immature structure called the procapsid. Genome loading leads to immense internal pressure, resulting in a conformational change from a spherical particle to an expanded, pressurized icosahedron. The extreme stability of P74-26 despite high temperature and pressure makes it a novel tool for elucidating the intricacies of phage assembly and thermodynamics. In this study, we will combine cryo-EM, SEC-multi angle light scattering, and mass spectrometry to examine physical and mechanistic aspects of P74-26. A structure of the uniquely long phage tail tube will provide perspective into the mechanism of DNA ejection and possible evolutionary advantages for such length. Additionally, we have found that the major capsid protein spontaneously assembles, allowing us to create a controlled system for determining the essential components for viral head stability.

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    Elucidating premature translation termination in Cystic Fibrosis

    A leading cause of Cystic Fibrosis (CF) is premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Suppression of translation termination at PTCs—i.e. PTC readthrough—to restore full-length CFTR protein may be a treatment strategy. Yet, current PTC readthrough drug candidates for CF are toxic (e.g. aminoglycosides) or ineffective (e.g. ataluren). Efficacy of PTC readthrough depends on efficiency of translation termination at the PTC. Thus, manipulating the molecular mechanisms of CFTR PTC termination to lower efficiency may improve PTC readthrough efficacy. However, strategies for such manipulations are limited in the absence of a detailed understanding of translation termination on CFTR PTCs. In the current model for normal termination, eukaryotic Release Factors 1 and 3 form a complex (eRF1•eRF3) that releases a newly synthesized protein from the ribosome. eRF1 recognizes a tetra-nucleotide stop codon at the end of an open reading frame, and catalyzes peptidyl-tRNA hydrolysis. Poly-A binding protein (PABP), which binds at 3′ ends of mRNA, recruits eRF3 and enhances termination efficiency. However, it remains unclear how PABP, eRF1, eRF3, and the tetra-nucleotide stop codon recognize the PTC to produce truncated CFTR protein. The goal of this proposal is to determine the biochemical and structural mechanism of translation termination. With guidance from Dr. Andrei Korostelev (expert in biochemical and structural mechanisms of translation), Dr. Allan Jacobson (expert in premature translation termination and PTC read-through), Dr. Phillip Zamore (RNA biochemist), Dr. Chen Xu (cryo-EM instrumentalist), and Dr. Nikolaus Grigorieff (expert in cryo-EM method development), release assays will be optimized to study the efficiency of translation termination mediated by eukaryotic release factors, and ensemble time-resolved (ENTIRE) cryo-EM will be used to capture structural intermediates of enzymatic reactions. Aim 1 will use defined mammalian translation systems to measure the individual effects of stop codon context, eRF1•eRF3, and PABP on the termination efficiencies (kcat/KM) of CFTR PTCs and the true stop codon. Aim 2 will visualize how the ribosome terminates on CFTR PTC G542X in its natural sequence context using ENTIRE cryo-EM. Collecting data at multiple time points will identify conformational changes and interactions between mRNA sequence, eRF1•eRF3, and PABP during termination. To reveal the termination mechanism on CFTR PTCs, structures and their progression intermediates will be compared with those recorded on the true CFTR stop codon. If successful, this study will reveal key molecular determinants of CFTR PTC termination, and may inform strategies to induce PTC readthrough for CF treatment.

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    A chemical biology approach to studying the role of SARM1 in a novel neuronal degradative pathway

    The novel NAD glycohydrolase, SARM1, is an active executioner in progressive axonal and neuronal degeneration1. This type of degeneration, termed Wallerian degeneration, defines a number of diseases, including neuropathies, traumatic brain injury and neurodegenerative diseases, yet no therapies exist. In fact, prior to the discovery of SARM1’s role in triggering Wallerian degeneration, the process was believed to occur passively. SARM1’s causal role in Wallerian degeneration demonstrates that it is an attractive therapeutic target that could prevent disease progression. However, the design of therapeutics targeting SARM1 is limited by the dearth of knowledge surrounding its inherent NADase activity. In order to evaluate SARM1’s therapeutic efficacy and design potential SARM1 inhibitors, the proposed research will study its structure, enzymatic mechanism and cellular activity. Solving the structure by leveraging the benefits of crystallography and cryoEM, determining the enzymatic mechanism via a series of assays and analyzing the in vivo activity with activity-based probes will fill in important gaps. Revealing these properties would enable the design of SARM1 inhibitors that could ultimately treat Wallerian-type diseases. Moreover, demystifying the role SARM1 plays in neurodegeneration would also allow for a better understanding of these disease types, the enzymatic capabilities of toll/interleukin receptor (TIR) domains and the involvement of NADases in numerous disease states.

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POST-DEGREE CAREERS

Biochemistry and Molecular Biotechnology graduates pursue a variety of career options.  Many go on to postdoctoral training and subsequent academic careers.  Others pursue opportunities in the pharmaceutical industry and biotech, with recent graduates taking positions at Vertex, Biogen, Pfizer, Moderna, and Genzyme, among others.  Biochemistry and Molecular Biotechnology graduates have also pursued diverse career paths, such as law, publishing and policy.