Throughout our lifetimes, from fertilized egg to adult, our cells must divide many times. To do that, cells must copy our whole genome of approximately three billion base pairs every time they divide. Special proteins come together to form a molecular machinery called the replisome, which unwinds the double helix of DNA in a cell, exposing the two strands and synthesizing a new, complimentary sequence of DNA for each.
“Imagine going through billions of these little ladders in just a few hours,” says Marcus B. Smolka, Molecular Biology and Genetics. “The replisome has to make a perfect copy. If it makes a mistake, mutations or chromosomal breakage result, and that is the hallmark of cancer.”
ATR—Monitoring the Replication Process
Many of the mutations that lead to cancer are in genes that make proteins required for replication and maintenance of the genome. Smolka and his lab study a class of proteins, known as kinases, with important roles in genome replication. They have found a particularly fruitful area of research in the kinase ATR, the master protein that monitors the replication process.
“If something goes wrong, ATR can detect it and will come to the region where the problem is,” Smolka explains. ATR is an enzyme, so it can modify other proteins by adding a phosphate to them. This phosphorylation starts a signaling cascade, a circuitry of events that orchestrates the detection and repair of damage before the cell divides in two.
“Before we started looking at this, people thought ATR worked in a linear pathway where it would target one protein, and that protein would target another protein,” Smolka says. “Our work has changed the paradigm of how the action of this kinase is viewed. It’s not a simple action; it’s really a network of events. ATR phosphorylates hundreds of different proteins.”
ATR and Cancer Cells
Understanding ATR’s fundamental role in replication is important for cancer research because cancer cells depend on ATR much more than normal cells do. “Cancer cells proliferate much faster than normal cells, which causes stress in the replication machinery and more chromosomal breakage, so they get addicted to ATR,” says Smolka. “They need it to repair the damage. If ATR is not there, they will die after one replication cycle. Replication in normal cells tends to be much more regulated and robust, so if you inhibit ATR a bit, normal cells will still be fine.”
Smolka’s research sheds light on work done by others in the scientific community who are focused on creating drugs that inhibit ATR. These drugs are currently in clinical trials for cancer treatment. “We’ve studied the action of ATR inhibitors, and they are very powerful,” says Smolka. “The problem is that researchers working on creating these drugs can see their effects—cancer cells die—but they don’t understand how the drugs do what they do. Our work is revealing what processes are being affected by the inhibitors.”
Techniques for Capturing ATR in Action
Part of Smolka’s basic research focuses on the action of kinases in yeast, which is a simple system that has analogous aspects with human biology. “We work in yeast and also in mammalian systems and human cell lines,” he says. “But it’s much easier to map the action of these kinases and come to a fundamental understanding of what they do in yeast. That gives us a powerful place from which to approach the understanding of human kinases.”
Smolka had to develop special techniques to capture the action of ATR and other kinases. To pinpoint ATR’s action in a cell, his lab uses mass spectrometry, which identifies the chemical constitution of a substance by separating ions according to their differing mass and charge.
“We can break open cells and extract pieces that make up the thousands and thousands of proteins,” he says. “To figure out what ATR is doing in cells, we are able to analyze these pieces of proteins and define which have the particular phosphate used by ATR to modify a target. That way we can map precisely where the phosphate is, and we can do it in a quantitative manner. That allows us to determine exactly what proteins ATR is targeting.”
Key Discoveries for Understanding Cancer
A key question Smolka and his colleagues want to answer centers on how ATR maintains the integrity of the genome. In 2017 they discovered that kinase promotes repair of chromosomal breaks in DNA. Kinase controls proteins that carry out the repair through the process of homologous recombination, where nucleotide sequences are exchanged between similar or identical molecules of DNA. “That was a very exciting finding,” Smolka says. “I think it will allow us to define the mechanism for how ATR works to prevent breakage to chromosomes.”
The researchers made another unexpected discovery that may also be a game changer for understanding cancer. They found that ATR can act in very different ways, depending on how it gets activated. When ATR is activated at a cell’s DNA break, it promotes DNA repair; when it is activated at other locations in the cell, it does not promote repair, but instead, it allows cells to replicate faster.
“This was a new function for ATR that we didn’t know about before. It could help explain why cancer cells are addicted to ATR.”
“This was a new function for ATR that we didn’t know about before,” Smolka says. “It could help explain why cancer cells are addicted to ATR. This kinase not only prevents chromosomal breakage, but it allows the replisome to go faster through the DNA so that cells replicate more quickly. We’re trying to figure out right now how it does that.”
Effective Cancer Therapies—Possible through Mapping the Action of Kinases
ATR is just one of many kinases the Smolka Lab studies. The researchers are turning their attention to several others in the VRK and TLK families that also appear to affect cancer cell replication. They are also continuing to branch out and improve the technology they use to map the action of kinases. They have begun using a genetic editing system known as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) that uses the nuclease Cas9 to target specific DNA sequences. “We are creating human cell lines where we can remove specific kinases,” Smolka explains. “We can then look at what set of target phosphates also disappear. That way we can map what each kinase does.”
The more scientists understand about the mechanisms behind how kinases work, the more applications for cancer therapy should result. To understand how cells replicate and maintain their stability—and why cancer cells are so good at it—the action of kinases must be understood from a more integrated perspective. “There are a lot of biology questions that are still unanswered,” Smolka says. “I think there is a huge potential to bring in new technology to understand these complicated systems from a holistic perspective and at the same time to bring the research down to a reductionist view and pinpoint a specific event. Our lab has the uncommon ability to do both these things.” Read more
Professor of cell biology Anthony P. Bretscher has been elected to membership in the American Academy of Arts and Sciences, along with Catherine Lord, professor of psychology in pediatrics at Weill Cornell Medicine in New York City.
One of seven newly elected members in cellular and developmental biology, microbiology and immunology, Bretscher joined the Department of Molecular Biology and Genetics in 1981. Read more
The Weill Institute for Cell and Molecular Biology is a hub for life science research at Cornell University. The institute’s mission is to understand fundamental cellular processes and human diseases through interdisciplinary biological research. Twelve faculty appointed to the institute hail from departments in the Colleges of Agriculture and Life Sciences, Arts and Sciences, and Engineering. They hold a range of technical expertise, including light and electron microscopy, crystallography, mass spectrometry, proteomics, lipidomics, systems biology, organic synthesis, electron cryomicroscopy, microfluidics, computational modeling, enzymology, genetics, and molecular biology. Read more
Scott D. Emr will give the 2017 Keith Porter Lecture at the 2017 ASCB|EMBO Meeting this December in Philadelphia. Emr is the Frank H.T. Rhodes Class of 1956 Professor of Molecular Biology and Genetics and the first director of the Weill Institute for Cell and Molecular Biology at Cornell University. The Porter Lecture is named for Keith Porter, a pioneer in the use of electron microscopy in biology and a founder of ASCB. Read more
Cells constantly interact with each other and with the surrounding extracellular matrix through physical forces such as tension, pressure, torque, and shear stress. Over the past 50 years, biologists have increasingly come to recognize the important role biomechanics plays in the function of cellular activities such as gene expression and signaling.
Here, The Scientist reports on recently developed methods—from upgraded versions of conventional tools to newer micro- and nanotechnologies—in the proliferating tool chest of cellular mechanobiology research. Read more
Nine doctoral candidates and one postdoctoral associate at Cornell were recently inducted into the Cornell chapter of the Edward A. Bouchet Graduate Honor Society. The 2017 Bouchet fellows are: Ezen Choo (pharmacology), Steve Halaby (biochemistry, molecular & cell biology), Frank He (biomedical engineering), Aaron Joiner (biochemistry, molecular & cell biology), Enongo Lumumba-Kasongo (science & technology studies), Paul Muniz (sociology), Ornella D. Nelson (chemistry and chemical biology), Suzanne Pierre (ecology and evolutionary biology), Gabriel J. Reyes-Rodriguez (postdoctoral scholar), Carrie Young (communication), and Christine Akoh (nutrition). Read more
A single gene is bringing researchers closer to understanding two devastating neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are both neurodegenerative diseases that ravage the body and brain. ALS attacks nerve cells, which in turn weaken muscles until they waste away, and FTLD damages the brain’s temporal and frontal lobes, leading to a loss in brain function and, ultimately, personality and behavior deterioration. While the causes of ALS and FTLD are still a mystery, both diseases share a common linkage in the gene C9orf72.
Peter Sullivan, a fifth-year doctoral student in the field of biochemistry, molecular, and cell biology, is working to better understand C9orf72 and how it functions to unravel the mystery of ALS and FTLD. Read more
What is the process that allows plant and animal organs to produce different specialized cells from an original set of identical cells? In the case of small and giant cells found in the sepals – the leaf-like covering of petals in a bud – of flowering Arabidopsis plants, the answer is randomness. Read more
Tobias Döerr, assistant professor, microbiology Academic focus: bacterial growth mechanisms Academic background: M.Sc., biology, University of Hannover, 2006; Ph.D., biology, Northeastern University, 2011 Previous positions: postdoctoral research fellow, Harvard Medical School and Brigham and Women’s Hospital/Howard Hughes Medical Institute, 2011-16 Last book read: “Bach: Music in the Castles of Heaven” by J.E. Gardiner In his own time: playing the guitar, spider taxonomy, comparative linguistics and learning new languages Read more
Sudeep Banjade, now a postdoctoral associate at Cornell University, won the ASCB Kaluza Prizes for Excellence in Graduate Research for his graduate work in Michael Rosen’s lab at the University of Texas Southwestern Medical Center where he studied the molecular mechanisms behind phase-separation of multivalent signaling proteins. He discovered that assembly of the adhesion receptor Nephrin and its cytoplasmic partners Nck and N-WASP leads to phase-separation in solution and on model membranes, which can activate this signaling system in a switch-like fashion. Read more
An essential molecule in cells, called phosphatidic acid (PA), is at the center of a cellular biology mystery.
This lipid, or fatty molecule, is a jack-of-all-trades – based on context, it can cause cells to move, divide or commit suicide. Elevated levels of PA have also been observed in many types of cancer as well as autoimmune and neurodegenerative diseases. Read more
Between the cracks in the sidewalk sprouts a thin, green stem with fragile white flowers. It is overlooked by the masses of people who walk past it each day. Unknown to these individuals, however, is the significance of the Arabidopsisplant within the scientific community. In her lab, Prof. Adrienne Roeder, a Nancy M. and Samuel C. Fleming Term Assistant Professor at the Weill Institute for Cell and Molecular Biology, uses the Arabidopsis sepal as a model system to study the spatial and temporal development of cells. Read more
What makes flowers on a plant almost identical, or internal organs remarkably reproducible? A study of sepals in Arabidopsis plants published in the July 11 issue of the journal Developmental Cell has revealed the mystery of how such uniformity occurs. Though the research was done on sepals – the bud that holds a plant’s reproductive organs – the researchers suspect similar mechanisms apply to organ development in all organisms. The study was conducted by an interdisciplinary team led by Cornell researchers. Read more
Graduate students and postdoctoral scholars [including Aaron Joiner, Fromme Lab] gathered in Stocking Hall recently to learn about a topic that’s strikingly absent at most universities: how to become a professor. Read more
Uncovering the details of a 100 million-year-old symbiosis between bacteria and whiteflies opens the door for controlling an insect pest that is rated one of the top 10 invasive species on the planet. Read more
Steve Halaby, a third-year doctoral student in the field of molecular biology and genetics, is passionate about educating the next generation and recruiting more minority students into science. “We need to invest in STEM now,” he said. Read more
Maggie Gustafson is a fifth-year doctoral student in the field of biochemistry, molecular and cell biology and this year’s winner of the Harry and Samuel Mann Outstanding Graduate Student Award. Her research in Chris Fromme’s lab is unlocking the secrets of a protein decision-making process that few knew existed until it was discovered at Cornell four years ago. Read more
Fromme has been selected as a Visiting Fellow of Clare Hall at the University of Cambridge, UK, where he will do sabbatical research at the Medical Research Council Laboratory of Molecular Biology. Read more
Cells perform some moves you definitely shouldn’t try in yoga class. As immune cells hunt down invading microbes, for example, they contort themselves to fit into the narrow gaps between other cells. Read more
Because they have narrow bodies and no collarbones, mice are able to squeeze through holes as small as a quarter-inch in diameter. Cancer cells similarly are able to migrate through extremely tight quarters but with a major difference: The journey often comes at a price – the deformation and, in some cases, rupture of the outer lining of a cell’s nucleus.
A research group headed by Jan Lammerding, associate professor of biomedical engineering, has been studying this phenomenon in hope of using it to develop both treatment and diagnostic solutions for the millions of people who deal with cancer every day. Read more
As the first person in her family to pursue a doctoral degree and a research career, Katherine Herleman did not know what to expect. During her first year at Cornell as an M.S./Ph.D. student in the field of geological sciences, she found herself “doing a lot of trailblazing” and relying on informal mentorship from her peers to find her way.
Aaron Joiner, a doctoral student in the field of biochemistry, molecular and cell biology, also found himself in need of peer guidance during his first year as he “struggled a lot with ‘impostor syndrome.’” Read more
Science Magazine asked young scientists to imagine that they could obtain unlimited funding for one currently unexplored scientific endeavor. What would they propose, and how would it revolutionize their field? Tommy Vo's answer was featured. Read more
Research on a modified protein around which DNA is wrapped sheds light on how gene regulation is linked to aging and longevity in nematodes, fruit flies and possibly humans. The research has implications for how gene expression is regulated, and could offer a new drug target for age-related diseases. Read more
Adrienne Roeder, Assistant Professor in Plant Biology, was one of twelve Cornell faculty members have been awarded research grants by the Affinito-Stewart Grants Program. The program, administered by the President’s Council of Cornell Women (PCCW), aims to increase long-term retention of women on the Cornell faculty by supporting the completion of research that is important in the tenure process. Read more
There is a growing awareness among biologists that the mechanical context of a cell determines some of its function. As a result of this awareness, many biologists are now looking outside of traditional biology and starting to focus on the mechanics and physics of cells. To do this, they are forging fruitful research relationships with engineers. Nowhere is this boundary-breaking collaboration more apparent than at Cornell’s Department of Biomedical Engineering. This trend in the field of biological research has made Cornell’s Jan Lammerding a very happy man. Read more
Each cell needs to constantly remodel the landscape of its surface because the thin membrane that surrounds all cells is fragile and must be renewed to protect the cell from lysis and death. And that’s where the trouble begins.
To remove aged and damaged cell-surface proteins, the membrane-sculpting macromolecular machine creates vesicles. These vesicles function as “molecular trash bags,” which carry old and misfolded membrane proteins from the surface into internal recycling plants, where the waste is degraded and components are reused.
That’s why Shaogeng Tang – a fourth-year doctoral student in the field of biochemistry, molecular and cell biology and recent recipient of the Harry and Samuel Mann Outstanding Graduate Student Award – is studying the ways these machines assemble and function to learn how to switch them on and off. Read more
From Yuxin Mao's lab: Phosphoinositide (PI) lipids regulate a wide variety of cellular processes, from cell signaling to cytoskeletal dynamics, by controlling the identity and properties of cellular membranes. A large number of PI kinases and phosphatases restrict the distribution of PI species and give each cellular compartment its own, distinct PI signature. When vesicles are transported from one compartment to another, therefore, their PI composition must be modified accordingly. Two papers by Hsu et al. and Nakatsu et al. reveal that the phosphatase Sac2 promotes endocytic trafficking by dephosphorylating PI(4)P (1, 2). Read more
Cornell researchers, led by Weill Institute Associate Professor Marcus Smolka, have developed a new technique to understand the actions of key proteins required for cancer cells to proliferate. The technique will help guide the development of drugs currently in clinical trials for anti-cancer treatments that inhibit this class of proteins, called kinases. Read more
On Nov. 10, Dean Kathryn Boor, Cornell Cooperative Extension Director and Associate Dean Chris Watkins, and more than 100 guests celebrated the College of Agriculture and Life Science’s best and brightest at the 11th annual Research, Extension and Staff Awards. Boor praised all the recipients, and thanked them for epitomizing Cornell’s land grant-mission of delivering knowledge with a public purpose.
Among those honored was Haiyuan Yu, one of two recipients of the Early Achievement award. Read more
Held in NYC for the first time, and hosted by Scott Emr (WICMB) and Frederick Maxfield, (WCMC), Weill Institute and Weill Cornell Medical College recently concluded the annual 3-day Symposium & Poster Presentations. Read more
Receiving more than $2.8 million to further their research, six early-career Cornell professors have been named recipients of the National Science Foundation’s Faculty Early Career Development Awards.
Prof. Richard Daziano, civil and environmental engineering; Prof. Jan Lammerding, biomedical engineering; Prof. Gregory Fuchs, applied and engineering physics; Prof. Ashutosh Saxena, computer science; Prof. John Foster, computer science; and Prof. Peter Frazier, operations research and information engineering were granted the prestigious award. Read more
Integrating techniques from both engineering and biology, Prof. Jan Lammerding, cell and molecular biology, biomedical engineering, is investigating how mutations in cell nuclear proteins cause conditions ranging from inherited heart disease to premature aging. Read more
This past summer, the Department of Plant Biology officially celebrated its centennial. The department, however, has been an important part of Cornell for more than 100 years, professors said. Read more
Cornell researchers have uncovered the basic cell biology that helps explain heart defects found in diseases known as laminopathies, a group of some 15 genetic disorders that include forms of muscular dystrophy and between 5 percent and 10 percent of all cases of inherited heart disease. Read more
To remove waste from cells, a class of membrane-sculpting proteins create vesicles - molecular trash bags - that carry old and damaged proteins from the surface of cellular compartments into internal recycling plants where the waste is degraded and components are reused. Read more
Prof. Adrienne Roeder, plant biology, is new to Cornell. She is continuing her postdoctoral work researching the role of cell division in the development of plant tissues. Roeder works in both the Department of Plant Biology and the Weill Institute for Cell and Molecular Biology. Read more
For the first time, a new computational method allows researchers to identify which specific molecular mechanisms are altered by genetic mutations in proteins that lead to disease.And they can apply this method to any genetic disease. Read more
TORC1 is a master regulator in cells, playing a key role in such diverse processes as gene expression and protein synthesis. While previous studies have described the role that TORC1 plays in these processes, a new Cornell study has discovered yet another process where the molecule is a central player. Read more
FoSheng Hsu, a graduate student in the field of biochemistry, molecular and cell biology and member of Yuxin Mao's lab, has won $500 for the best dance in the chemistry category in Science's fourth annual "Dance Your Ph.D." contest, a competition that recognizes the best dance interpretations of scientific doctoral work. Read more
Although all cells in an organism have the same DNA, cells function differently based on the genes they express. While most studies of gene expression focus on activities in the cell's nucleus, a new Cornell study finds that processes outside the nucleus -- along the membrane -- also play important roles in gene expression. Read more