Tag Archive for Hingorani

Hingorani, Lui, Zhou PhD ’13 Published in Biological Chemistry Journal

Three scholars from the Molecular Biology and Biochemistry Department are co-authors of a study published in The Journal of Biological Chemistry in August 2017. The paper is titled “Linchpin DNA-binding residues serve as go/no-go controls in the replication factor C-catalyzed clamp loading mechanism.”

The co-authors, Manju Hingorani, chair and professor of molecular biology and biochemistry, professor of integrative sciences; Juan Liu, research associate; and Zayan Zhou, PhD ’13, performed the study on Replication Factor C (RFC) and proliferating cell nuclear antigen (PCNA), which are two essential proteins required for DNA replication and repair in all living organisms.

The researchers found new mechanistic information about how different parts of the RFC protein work together to load PCNA onto DNA (by “clamp loading”), which allows PCNA to help dozens of other proteins to replicate and repair DNA.

The Hingorani group investigates proteins responsible for DNA replication and repair. These proteins maintain genome and cell integrity, and their malfunction leads to cancer and other diseases.

Researchers’ Paper Selected as “Editor’s Choice” by American Chemical Society

jp-2016-11976k_0007Three faculty and one graduate student co-authored a paper titled “Statistical Coupling Analysis combined with all-atom Molecular Simulation Postulates Dynamical Allosterism in the MutS DNA Mismatch Repair Protein,” published in the March issue of the Journal of Physical Chemistry – Biophysics, published by The American Chemical Society.

The authors include David Beveridge, the Joshua Boger University Professor of the Sciences and Mathematics, professor of chemistry, professor of integrative sciences; Manju Hingorani, professor of molecular biology and biochemistry, professor of integrative sciences; Kelly Thayer, visiting assistant professor of computer science; and molecular biology and biochemistry graduate student Bharat Lakhani.

This project is part of Lakhani’s ’16 PhD thesis of Lakhani. Notably, the project brings together the experimental biochemistry of Hingorani’s research program, which specializes in DNA mismatch repair, and the computational biophysics in Beveridge’s Laboratory, which specializes in molecular dynamics simulations. All theoretical calculations were carried out using the Wesleyan High Performance Computer Cluster.

In addition, the article was selected as an ACS “Editor’s Choice,” an honor given to one article from the entire ACS portfolio of journals each day of the year. As a consequence, the authors have been invited to submit a 30-40 minute online presentation to “ACS LiveSlides,” which increases the exposure of the published work.

Hingorani Finishes Program Director Appointment with NSF

Manju Hingorani

Manju Hingorani

Manju Hingorani, professor of molecular biology and biochemistry, professor of integrative sciences, recently completed a two-year tenure working for the National Science Foundation’s Division of Molecular and Cellular Biosciences (MCB). Hingorani served as the program director of the MCB Genetic Mechanisms program.

Hingorani worked with investigator-driven proposals submitted to both the Genetic Mechanisms and the Cellular Dynamics and Function programs. As a rotating program director, Hingorani managed proposal reviews and awards and responded to inquiries from principal investigators conducting fundamental research related to the central dogma of biology.

Hingorani Reflects on Marriage, Career in Biochemistry and Molecular Biology Journal

In 2015, Manju Hingorani and her husband of 19 years, Anish Konkar, met up in Helsinki after Hingorani attended a conference in Oslo held in honor of this year’s Nobel laureate Tomas Lindahl. They then traveled to St. Petersburg, Russia, and Tallinn, Estonia.

In 2015, Manju Hingorani and her husband of 19 years, Anish Konkar, met up in Helsinki after Hingorani attended a conference in Oslo held in honor of this year’s Nobel laureate Tomas Lindahl. They then traveled to St. Petersburg, Russia, and Tallinn, Estonia.

Manju Hingorani, Wesleyan professor of Molecular Biology and Biochemistry, was featured in the “Coordinates” section of ASBMB Today, the monthly publication of the American Society for Biochemistry and Molecular Biology. Here, Hingorani briefly reflected on her marriage and career through a haiku.

Her haiku read:

Home is where the lab

is, was, will be, my partner

he’s home too – elsewhere.

She added, “I’m a professor of biochemistry, and my husband is a pharmacologist in the industry. We’ve lived under the same roof for about seven of our 19 years as a married couple. But it has been a fabulous life, doing what we love and meeting up for a few days/weeks/months at a time in different cities around the U.S. and the world. We wouldn’t change a thing.”

The link to the full article: http://www.asbmb.org/asbmbtoday/201602/Coordinates/

 

Hingorani’s DNA Mismatch Study Published in PNAS

Manju Hingorani

Manju Hingorani

Manju Hingorani, professor of molecular biology and biochemistry, is the co-author of “MutL Traps MutS at a DNA Mismatch,” published in the July 21 issue of the Proceedings of the National Academy of Sciences (PNAS). Postdoctoral researcher Miho Sakato also co-authored the article.

DNA mismatch repair is the process by which errors generated during DNA replication are corrected. Mutations in the proteins that initiate mismatch repair, MutS and MutL, are associated with greater than 80 percent of hereditary nonpolyposis colorectal cancer and many sporadic cancers. The assembly of MutS and MutL at a mismatch is an essential step for initiating repair; however, the nature of these interactions is poorly understood.

In this study, Hingorani, Sakato and their fellow researchers discovered that MutL fundamentally changes the properties of mismatch-bound MutS by preventing it from sliding away from the mismatch, which it normally does when isolated. This finding suggests a mechanism for localizing the activity of repair proteins near the mismatch.

 

Hingorani Awarded Major NIH Research Grant

Manju Hingorani, professor of molecular biology and biochemistry, was awarded a grant of $408,609 from the National Institutes of Health (NIH) to study the structure and mechanisms of DNA repair proteins responsible for fixing errors in the genetic code and preventing carcinogenesis.

The three-year grant will fund PhD and undergraduate students’ research on DNA mismatch repair (MMR). MMR corrects base mismatches and loops in DNA, and is therefore a critical guardian of genetic and cellular integrity. Defects in this essential, evolutionarily conserved DNA repair process cause high levels of mutations in the genome, which in turn lead to cancer. In humans, MMR defects manifest most frequently in a hereditary disorder known as Lynch Syndrome (LS), which substantially raises the risk of colorectal, endometrial and many other cancers.

A large number of MMR defects occur due to small, single-amino-acid changes in the MutS protein that initiates the repair reaction. Hinagorani’s research group has been investigating MMR proteins for the past 15 years. The group now has a detailed enough understanding of the MutS biochemical mechanism to determine how changing single amino acids affects MutS structure and function enough to disrupt MMR. In addition to experimental research, the project also builds on computational modeling done in collaboration with Joshua Boger University Professor of the Sciences and Mathematics David Beveridge’s group in the Chemistry Department, and Professor Saraswathi Vishveshwara’s group at the the Indian Institute of Science in Bangalore, India. Beverage is also professor of chemistry. The researchers hope that by applying biochemical, biophysical and computational approaches in an interdisciplinary manner, students will gain new knowledge about MutS function and, thereby, a better understanding of the basis for its malfunction in cancer.

Hingorani Serves as NSF Program Director for the Biosciences

Manju Hingorani

Manju Hingorani

Manju Hingorani, professor of molecular biology and biochemistry, is serving as the rotating program director at the Division of Molecular and Cellular Biosciences (MCB) at the National Science Foundation in Washington, D.C. Her rotation concludes in August and she will resume teaching next fall.

The MCB supports quantitative, predictive and theory-driven fundamental research and related activities designed to promote understanding of complex living systems at the molecular, subcellular and cellular levels. MCB gives high priority to research projects that use theory, methods and technologies from physical sciences, mathematics, computational sciences and engineering to address major biological questions. Typical research supported by MCB integrates theory and experimentation.

“I look forward to advancing science from this very different and much broader perspective than usual. And it would be nice to become a more effective advocate for basic research and science education after this experience,” she said.

 

State Grant will Support Hingorani’s Research on Lynch Syndrome

Manju Hingorani

Manju Hingorani

Manju Hingorani, professor of molecular biology and biochemistry, received a grant worth $324,127 from the State of Connecticut Department of Public Health on May 1.

Hingorani will use the grant to address an important need for new diagnostic technology for Lynch Syndrome (LS), a genetic disorder involving malfunction of DNA mismatch repair, which substantively increases the risk of colorectal, endometrial and other cancers. About 150,000 patients are diagnosed with colon cancer in the U.S. per year, of whom more than one in 35 have LS, and three or more of their relatives are at risk for the disorder (about one in 500 Connecticut residents).

“Early diagnosis of LS can profoundly affect the way in which cancer patients are treated—with respect to surgery, chemotherapy and future surveillance—and provide analogous benefits to their family,” Hingorani explained.

Current validated tests for LS have limitations that lower their feasibility and widespread use in screening at-risk populations.

“Our hypothesis is that the core functions of MMR proteins can be measured directly, quantitatively, rapidly, reliably and at clinically relevant protein concentrations on a nano-structured surface,” she said.

This project, proposed in collaboration by investigators Hingorani and Prabir Patra, assistant professor of mechanical engineering and director of the Biomedical Engineering Program at the University of Bridgeport, is expected to enable development of novel diagnostic nanosensors that will enable substantive advances in the screening, diagnosis and treatment of colorectal and other cancers.

Hingorani’s DNA Repair Studies Published in Journals

Manju Hingorani, professor of molecular biology and biochemistry, is the author of “Distinct structural alterations in proliferating cell nuclear antigen block DNA mismatch repair,” published in Biochemistry on Aug. 20, 2013. Read an abstract of the paper online here.

She’s also the author of “Slow Conformational Changes in MutS and DNA Direct Ordered Transitions between Mismatch Search, Recognition and Signaling of DNA Repair,” published in The Journal of Molecular Biology on Aug. 20, 2013. Her former students, F. Noah Biro ’09 and Christopher Doucette ’11 co-authored the paper. Read the abstract online here.

Taylor, Hingorani, Students Co-Author Paper in Biochemistry Journal

Two faculty members and two graduate students co-authored a paper published in the July 18 edition of the academic journal, Biochemistry.

Erika Taylor, assistant professor of chemistry, assistant professor of environmental studies; Manju Hingorani, professor of molecular biology and biochemistry; chemistry graduate student Daniel Czyzyk; and molecular biology and biochemistry graduate student Shreya Sawant wrote the paper, “Escherichia coli Heptosyltransferase I: Investigation of Protein Dynamics of a GT-B Structural Enzyme.”

It appears online here.

Biochemistry is a publication of the American Chemical Society.

Hingorani Group Publishes 8 Papers on DNA Mismatch Repair

A research group led by Manju Hingorani, associate professor of molecular biology and biochemistry, has published eight papers in 2011-2012 on the mechanisms of DNA replication and repair proteins, independently and in collaboration with research groups at Wesleyan and other national and international universities.

The papers are:

“Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signaling,” published in The EMBO Journal, 2012 (in press).

The Variable Sub-domain of Escherichia coli SecA functions to regulate in the SecA ATPase Activity and ADP release,” published in the Journal of Bacteriology, 2012 (March 2 Epub). Don Oliver, the Daniel Ayres Professor of Biology, professor of molecular biology and biochemistry, was the lead investigator and Fred Cohan, professor of biology, professor of environmental studies, was a co-author on this paper.

Single-molecule multiparameter fluorescence spectroscopy reveals directional MutS binding to mismatched bases in DNA,” published in Nucleic Acids Research, 2012 (Feb, 24 Epub).

Biochemical analysis of the human mismatch repair proteins hMutSαMSH2G674A-MSH6 and MSH2-MSH6T1219D,” published in the Journal of Biological Chemistry, 2012 (Jan. 25 Epub).

ATP Binding and Hydrolysis-Driven Rate-Determining Events in the RFC-Catalyzed PCNA Clamp Loading Reaction,” published in the Journal of Molecular Biology, Feb. 17, 2012; 416(2), pages 176-91.

A Central Swivel Point in the RFC Clamp Loader Controls PCNA Opening and Loading on DNA,” published in the Journal of Molecular Biology, Feb. 17, 2012; 416(2), pages 163-75.

Human MSH2 (hMSH2) protein controls ATP processing by hMSH2-hMSH6,” published in the Journal of Biological Chemistry, Nov. 18, 2011; 286(46), pages 40287-95.

Dynamical allosterism in the mechanism of action of DNA mismatch repair protein MutS,” published in the Biophysical Journal, Oct. 5, 2011;101(7), pages 1730-9. David Beveridge, the Joshua Boger Professor of the Sciences and Mathematics, was the lead investigator on this paper.

DNA Studies by Hingorani, Beveridge Published in Journals

Manju Hingorani, associate professor of molecular biology and biochemistry, co-authored a study titled “hMSH2 controls ATP processing by hMSH2-hMSH6,” published in the Journal of Biological Chemistry on Sept. 19. The abstract is online here.

Hingorani co-authored another study with David Beveridge, the Joshua Boger University Professor of the Sciences and Mathematics, professor of chemistry, titled “Allosterism in Muts Proteins: How DNA Mismatch Recognition Signals Repair.” The study was published in the Biophysical Journal in 2011. The abstract is online here.