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Biochemistry and Molecular Pharmacology Program

The Graduate Program in Biochemistry and Molecular Pharmacology 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 Pharmacology program must take 3 elective courses (2-4 credits), two of which must be part of the BMP 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

Nick Rhind.jpgNick Rhind, PhD
Professor
email Dr. Rhind  |  Learn more about the Rhind 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 inlcude:

  • 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 Pharmacology Program.

OUR STUDENTS

The Graduate Program in Biochemistry and Molecular Pharmacology is an integral part of the Department of Biochemistry and Molecular Pharmacology.  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.

OUR STUDENTS IN THE NEWS

Getting Results…
  • PhD candidate Yvonne Chan a ‘protein engineer’
    Media, Research News

    PhD candidate Yvonne Chan a ‘protein engineer’

    In this Women in Science video, PhD candidate Yvonne Chan talks about her exploration of how proteins fold and maintain their three-dimensional structure.

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EXTERNAL AWARDS FOR RESEARCH TRAINING (CURRENT)

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    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 replication 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 collaborate 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 compromise 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 and a series of anisotropy experiments to capture the different states of 9-1-1 loading. Collectively, our work will help in the development of sliding clamp specific chemotherapeutics and tumor diagnostics.

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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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  • Carbone.jpg

    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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EXTERNAL AWARDS FOR RESEARCH TRAINING (PAST)

  • Sheel.jpg

    Exploiting RNAi-based silencing of Myc and metabolic vulnerabilities to prevent relapse afer Kras inhibition in lung cancer

    Lung cancer is the leading cause of cancer-related death, accounting for approximately 1.3-million deaths worldwide. The most common type of lung cancer, non-small cell lung cancer (NSCLC), is frequently associated with oncogenic mutations in KRAS, a GTPase that regulates cell growth and division. Oncogenic KRAS mutations constitutively activate Kras protein and result in rapid cell division, even in the absence of growth signals, and thus play a critical role in tumor formation and maintenance. Genetic inactivation of oncogenic Kras reduces tumor size and metastatic potential, but Kras-independent tumors eventually recur and are more aggressive. Preliminary studies suggest that Kras-independent relapse may be mediated by the proto-oncogene, MYC. The MYC mRNA is a known target of the microRNA miR-34a, and treatment with ectopic miR-34a delays Kras-independent relapse. The goal of the proposed project is to understand the roles of Myc and miR-34a in Kras-independent tumor relapse in a mouse model of NSCLC. Aim 1 will investigate the role of miR-34a in delaying relapse. Endogenous levels of miR-34a will be quantified during tumor growth and regression, and during Kras-independent relapse. CRISPR/Cas9 genome editing will be used to mutate the miR-34a binding site in the Myc 3’ untranslated region to test whether miR-34a delays relapse by directly silencing Myc. Findings from this aim will provide insight into the use of microRNA-mediated inhibition as a potential therapeutic strategy to target Myc. Aim 2 will investigate how Myc controls relapse and glucose metabolism in Kras-independent NSCLC cells and mice. To achieve this, a novel doxycycline inducible dual shRNA system will be used to co-silence Kras and Myc expression in vitro. Using the seahorse bioanalyzer system, glucose metabolism will be monitored in both Kras-silenced and Kras/Myc co-silenced NSCLC cells to identify metabolic vulnerabilities of tumors. Using a mouse model of NSCLC, tumor burden will be monitored after Kras and Kras/Myc co-silencing. This aim will result in a novel dual shRNA based strategy to establish the efficacy of co-silencing Myc and Kras as a therapeutic strategy to induce tumor regression and prevent relapse in NSCLC. Taken together, findings from this study will elucidate mechanisms of tumor relapse induced by Kras silencing and identify regulators of tumor development, maintenance, and relapse. Ultimately, this work will aid in the creation of novel therapeutic strategies to improve NSCLC patient outcomes.

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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 Pharmacology 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 Pharmacology graduates have also pursued diverse career paths, such as law, publishing and policy.