Ohio State News

Best snapshots yet of DNA repair protein relevant to BRCA mutations

Mon, 27 Apr 2026 12:04:18 -0400

Scientists have captured the most detailed structural images to date of a specific type of protein’s DNA repair process, a finding that could reveal ways to inhibit the effects of BRCA1 and BRCA2 mutations that heighten the risk for breast, ovarian and other cancers.

Previous research has shown that a protein in humans called RAD52 performs DNA repair in cancer cells lacking the tumor-suppression function of normal BRCA genes, enabling the cells to survive and replicate – an indication that blocking RAD52 would kill these cells.

But blocking RAD52 requires fully understanding its repair activities, which have been difficult to capture with even the most sophisticated techniques. So the research team turned to its ancestral protein Mgm101 in yeast mitochondria and observed several key steps in its DNA repair process, called single-strand DNA annealing.

A clearer understanding of how this family of proteins binds to DNA strands and coaxes them back together after a break provides insights for drug targets that could halt the process in cancer cells empowered by mutated BRCA genes.

“It’s still a proposed mechanism: Just because we see these snapshots of the process doesn’t mean we know all the details, but we do have the best snapshots for any protein that does this single-strand annealing,” said senior author Charles Bell, professor of biological chemistry and pharmacology at The Ohio State University College of Medicine. “This focuses our strategies for drug development.”

The study is published today (April 27, 2026) in the journal Nucleic Acids Research, which designated the paper as a Breakthrough Article.

DNA strands break every day in every cell, which is why proteins exist to fix the breaks and otherwise keep cellular processes running smoothly. But because repairs must happen quickly and human proteins are often more complex than their ancestral counterparts, even the most advanced imaging equipment can’t capture every step in the process.

Bell’s lab partnered on this research with the lab led by co-author Vicki Wysocki, professor emerita at Ohio State and chair of the School of Chemistry & Biochemistry at the Georgia Institute of Technology. Wysocki’s lab specializes in native mass spectrometry and mass photometry, using light to measure masses of protein-DNA complexes.

These techniques showed that Mgm101 assembled from a monomer, or single copy of itself, into a large multi-unit molecular complex called a 19-mer – essentially, a ring composed of 19 copies of the protein.

“This ring is sitting there as a template so that the first strand of the DNA can come down, and then the second strand comes on and starts being annealed to the first strand,” Wysocki said.

These findings were supported by what Bell’s lab determined using cryogenic electron microscopy, observing structures floating in solution and frozen in a thin layer of ice.

The high-resolution structures showed multiple phases of the process: the 19-mer ring with a single strand of DNA attached (substrate), with the second strand in place for annealing (duplex intermediate), and after release of the repaired DNA, visible as the classic double helix DNA formation (B-form product).

“RAD52 high-resolution structures have been determined with single-stranded DNA, but not with the two DNAs that it’s trying to anneal,” Bell said. “Its job is to bind single stranded DNA and anneal it to its complement sequence. It’s been captured structurally, but only in a few states relevant to the reaction.

“Here, we have more of the states along the full pathway from substrate, to intermediate and product. And the duplex intermediate is a conformation that’s never been seen before – when the protein binds the first DNA around the ring, it’s bound only by its sugar-phosphate backbone, with the nucleotide bases pointing up and fully exposed and separated, so that they can be searched. It’s extended, it’s completely unwound, and it’s circular.”

Bell said the field has been uncertain about whether this mechanism is carried out with one or two participating protein rings, but that these findings show the process is managed by a single molecular complex – and, therefore, single-strand annealing is likely to be a conserved cis mechanism.

The team plans to try to capture the same phases of the DNA repair process with RAD52 from humans, placing particular emphasis on the duplex intermediate, and to expand the role of mass spectrometry in determining how the DNA is bound to the protein.

This work was supported by the U.S. National Science Foundation and the National Institutes of Health. The cryo-EM data were collected at Ohio State’s Center for Electron Microscopy and Analysis and processed using the Ohio Supercomputer Center.

Carter Wheat of Ohio State and Zihao Qi, formerly of Ohio State and now at Georgia Tech, are co-first authors of the study. Additional co-authors include Metro High School student Miqdad Hussain and Katerina Zakharova, formerly of Ohio State and now at CAS.

Why undisturbed sleep is important to brain injury recovery

Tue, 02 Dec 2025 13:27:42 -0500

A new study highlights how important uninterrupted sleep is to recovery after a traumatic brain injury, finding that fragmented sleep in injured mice is linked to a loss of rapid-eye-movement (REM) sleep and increased fatigue.

Specifically, the research shows that fragmented sleep worsens symptoms that a traumatic brain injury (TBI) alone produces – and that mice without a head injury can make up for some REM sleep loss brought on by interruptions to sleep, but injured mice do not.

REM sleep has a major role in helping the brain consolidate and process new information and is associated with better concentration and mood regulation. Loss of REM sleep can lower brain and cellular function.

“I think sleep has gone underappreciated as a key determinant of traumatic brain injury outcomes for a long time,” said senior author Olga Kokiko-Cochran, an investigator in the Chronic Brain Injury Program and the Institute of Brain, Behavior, and Immunology (formerly the IBMR) at The Ohio State University and associate professor of neuroscience in the College of Medicine.

“A brain injury doesn’t occur in isolation. We have to think about the recovery environment and acknowledge that there are effects of external stimuli,” she said. “We set up the paper to think about recovery in a hospital, rehabilitation or even a home setting where there are lots of things in the environment that might influence someone’s sleep – and oftentimes those may go unrecognized or unnoticed or even downplayed as to how important they could be in influencing recovery.”

The research was published recently in the journal Experimental Neurology.

Injuries in this work were moderate in severity and resembled the type of TBI that could result from a fall – the most common cause of traumatic brain injury.

The experiments involved four groups of mice: those with a TBI (performed surgically under anesthesia) exposed to either sleep fragmentation or no sleep disturbance, and “sham” mice, which had surgery but no brain injury, that got either normal or fragmented sleep.

Select mice from each group were implanted with telemetry sensors to detect brain (EEG) and muscle (EMG) activity, body temperature and cage activity for 30 days after the surgery or injury – the equivalent of several months in a human.

Sleep was interrupted in the sleep fragmentation groups by a bar that swept across the floor of the mouse cage every two minutes during the first four hours of the animals’ sleep phase – intended to mimic a period when sleep need is high, such as when a patient might have trouble falling asleep in a clinical setting.

Results showed that after about a week, mice with TBI were less active than uninjured mice, and their activity continued to decrease over weeks three and four. Sleep fragmentation alone also brought on fatigue – but interrupted sleep on top of the TBI significantly intensified the fatigue.

Analysis of data on the animals’ biological rhythms showed there was more to the story of TBI coupled with interrupted sleep: changes to their rest-activity patterns over time.

“Just looking at the activity alone you can’t differentiate that the fatigue is worse until you look at some more nuanced statistical tests,” said Christopher Cotter, co-first author of the paper and a student in Ohio State’s Neuroscience Graduate Program. “That’s really important when we think about clinical populations – they might get sleep recordings that suggest nothing is wrong. One of the points of this analysis was to show that there are a lot of biological things happening that you may not be able to see with sleep analysis alone.”

Sleep fragmentation affected both non-REM and REM sleep in all of the mice, which was not a surprise. The analysis of interrupted sleep on the REM phase focused on what recovery looked like in the mice after the fragmentation exposure stopped.

Findings show that mice with TBI and TBI with fragmented sleep displayed decreased REM sleep, while uninjured mice with sleep fragmentation made up for the sleep loss.

“So the sham mice are compensating for the loss, but all of the animals with TBI are not compensating for that loss and they continue not compensating for the loss over the four weeks. They just lose that REM sleep and they don’t get it back,” Cotter said. “We looked to see if they were sleeping more when they were not supposed to be, and the answer was no. So they just lost that sleep, and that was a really striking finding.”

The EEG provided data on electricity released by different structures of the brain that are associated with specific biological functions. Results showed that injured mice with interrupted sleep had deficits not seen in uninjured mice: These animals had an increased need for non-REM sleep but didn’t get more non-REM sleep, and their loss of REM sleep – especially in the acute recovery phase – could be linked to loss of cognitive function.

“Change in sleep quality really happens between one and 14 days, so that is a more vulnerable time for disruption after traumatic brain injury,” Cotter said. “There is this sensitized injury response period.”

Kokiko-Cochran said the collection of 30 days of continuous EEG and EMG data provided insights that will enhance future sleep-related TBI research in her lab.

“This model of brain injury and sleep fragmentation gives us an opportunity to study things like fatigue – something understudied in the space of traumatic brain injury that can be difficult to model,” she said. “It’s important because many survivors have an opportunity for extended lifespans. They’re surviving sometimes decades after their brain injury, but there are still persistent symptoms.

“We are trying to be conscious of the fact that people are having lots of other experiences that could influence their recovery.”

This work was supported by the National Institutes of Health.

Additional co-authors, all from Ohio State, included co-first author Zoe Tapp, Cindy Ren, Sam Houle, Jessica Mitsch, John Sheridan, Jonathan Godbout, Juan Peng and Ashley Ingiosi.

For dying patients, early plans can improve quality of life

Thu, 06 Jun 2019 07:30:00 -0400

Careful documentation of a hospice patient’s end-of-life wishes – and prominently noting that information in health records early – could prevent unwanted hospitalizations and medical interventions, a new study suggests.

Researchers at The Ohio State University analyzed the health records of 1,185 cancer patients who had been referred to hospice and found that a verified do-not-resuscitate order, or DNR, before the last 30 days of life reduced the odds of hospitalization. A prominent note in the electronic health record indicating advanced care planning (for example, discussions with providers on legal directives, a living will or a health care power of attorney) also reduced the chances of admission – especially if that note was made at least six months prior to death.

Once a terminally ill patient transitions into hospice care, the goal is to avoid hospitalizations and procedures that are unnecessary and unwanted, said Laura Prater, the study’s lead author and a postdoctoral researcher in the Division of General Internal Medicine at Ohio State’s College of Medicine.

The aim is twofold: to respect the wishes of the patient and to focus on quality of life and pain management. On top of that, keeping hospice patients out of the hospital reduces medical costs.

“Our research supports the importance of sharing your wishes with your physician and your family, and suggests that doing that earlier can prevent unwanted procedures and hospitalizations that don’t align with your priorities and deteriorate your quality of life,” Prater said.

The study was recently published online in the American Journal of Hospice & Palliative Medicine.

It’s important for physicians and others on a patient’s care team to have conversations that address that person’s values and goals, including what to do if his or her illness is no longer treatable, said Seuli Bose-Brill, the study’s senior author and an Ohio State Wexner Medical Center primary care physician who specializes in internal medicine and pediatrics.

“These study results really support the idea that earlier is better for documenting these wishes. Those who had advanced care planning notes in their health records six months or more before a hospital trip were significantly less likely to be admitted,” Prater said.

Specifically, the researchers looked at the “problem list” on the medical record – an easy-to-spot synopsis of that person’s health status. When advanced care planning was noted there more than six months before the final month of life, hospitalization was least likely.

Previous studies have found that only 13 to 44 percent of terminally ill patients have documentation of advanced care planning in their electronic health records and that the location and ease of finding that documentation is inconsistent.

In times of crisis, hospice patients often are not in a position to advocate their own priorities and family members can be unsure, afraid or in disagreement about those wishes, complicating matters. When the medical team can easily see in the electronic health record that the patient has documented his or her wishes, it eases their ability to act in the patient’s best interest, Bose-Brill said.

“I think everyone in medicine is aware that we need to do a better job documenting end-of-life wishes, but as a nation we haven’t figured out how best to do that,” she said.

Prater said this study could prompt discussions within medical practices and hospitals about how to consistently discuss and document advanced care planning for patients.

“It’s important to make this part of the process, to look for ways to make sure that these conversations are happening consistently, early and often, even though they are complex and difficult conversations to have,” Prater said.

And the topic shouldn’t only come up when transitioning to hospice, Bose-Brill said, because that is a time that can be particularly fraught with emotion and grief and not always the best opportunity to broach the subject.

“The earlier we start this process, the more it normalizes it,” she said.

“There are so many opportunities to explore these issues that patients and families are grappling with and we in health care need to not absolve ourselves of our responsibility to talk about these things.”

Thomas Wickizer and Julie Bower of Ohio State’s College of Public Health also worked on the study.

Harold L. Paz, M.D., named executive vice president and chancellor for health affairs at Ohio State

Wed, 20 Feb 2019 10:20:21 -0500

The position of chancellor for health affairs at The Ohio State University will be held by a nationally renowned executive with an unparalleled combination of expertise in both academic medical center leadership and Fortune 50 company business development.

President Michael V. Drake announced today that Dr. Harold L. Paz, who for 20 years led major medical programs at two large public universities through unprecedented growth, will be the first to serve in the position of executive vice president and chancellor for health affairs at Ohio State, pending Board of Trustees approval. He will join the university this spring.

Paz is recognized as a visionary leader who advocates a comprehensive model to address health and wellness of individuals and communities in a rapidly evolving society.

Paz is a former leader of the health care enterprise at Penn State University, where he served as CEO of the Penn State Milton S. Hershey Medical Center, senior vice president for health affairs, dean of the College of Medicine and president/CEO of the Penn State Hershey Health System from 2006 to 2014.

He left Penn State to join Aetna, a managed health care company based in Hartford, Connecticut, as executive vice president and chief medical officer, providing clinical leadership for the company’s domestic and global businesses. Since 2015, he has also been a professor adjunct of internal medicine at Yale University School of Medicine. He remains clinically active, volunteering as a pulmonary physician at the Veterans Administration Medical Center in West Haven, Connecticut.

Paz said the time is right to return to academic medicine, and specifically Ohio State, which he described as a university “poised to be at the cutting edge of addressing dramatic changes in health care delivery and health professions education.”

“Effective delivery of health care in America must include nontraditional settings to meet people’s needs and take into account the range of determinants of health. Behavioral, social, environmental, financial and genetic factors all influence every person’s health status,” he said.

“A comprehensive flagship university like Ohio State can marshal all of its resources and intellectual prowess in fields as diverse as the health sciences, economics, social work, agricultural extension and even climate science to identify solutions. Ohio State is at the forefront of defining the future and educating the next generation of health care professionals for a very different world.”

Drake said Paz stood out among chancellor candidates in the university’s national search because of his track record as a proven leader in academic medicine, and his clear vision for Ohio State — enhanced significantly by his private-sector navigation of consumer-driven personalized health care.

“Throughout the search process, we were determined to find the exact right fit, not just for the job requirements, but for Ohio State,” Drake said.

“We are fully committed to the foundation of evidence-based academic medicine, rigorous biomedical research and interprofessional education in all of the health sciences. Dr. Paz embodies those priorities. He also brings to the position an openness to new ways to make bold advances. That portfolio is a perfect fit for a medical enterprise that employs top talent and is seeing historic highs in research funding and productivity, innovative medical training, and patient-care quality and demand.”

“The hard work of the staff and leadership that got us from where we were to where we are has been significant. Now the aspiration is to accelerate and build on that sound foundation,” said Leslie H. Wexner, chair of the Wexner Medical Center Board, as he introduced Paz at the board meeting today.

“This is a momentous day for Ohio State and its medical center.”

Paz applied his personalized health focus at Aetna, emerging as an innovative tactician in the fight against opioid abuse by analyzing member physician data to identify so-called “super-prescribers” of narcotic painkillers. The company provided a pain medication prescription checklist to these member doctors and advised them to follow Centers for Disease Control and Prevention guidelines when prescribing opioids for chronic pain. He described the Aetna program in the 2018 PBS documentary “Understanding the Opioid Epidemic.”

At Ohio State, Paz will manage the $3.7 billion Ohio State University Wexner Medical Center enterprise, including all seven hospitals in the health system. He will also oversee the university’s seven health-sciences colleges in partnership with the provost and more than 20 research institutes. Academic health care is one of five key focus areas outlined in the Time and Change Strategic Plan, and Paz will be responsible for ensuring that Ohio State continues its ascent as a leading academic health center. His base salary will be $1.45 million.

Paz will arrive at a time of dramatic growth. Ohio State is at various stages of planning and design for a Wexner Medical Center inpatient hospital, an interdisciplinary health sciences center and a west campus ambulatory center that will include central Ohio’s first proton therapy treatment facility in partnership with Nationwide Children’s Hospital. Additionally, ambulatory locations are being planned in northeast Columbus, Powell and Dublin. And the College of Medicine is in the midst of an ambitious plan to hire 500 faculty.

“Ohio State is on an extraordinary trajectory serving the communities of Ohio as a result of its exceptional leadership, faculty, clinicians and employees,” Paz said. “It is truly an honor to join the team of an outstanding institution that has enormous impact.”

While at Penn State, Paz oversaw unprecedented growth in the medical center’s operating budget and construction of eight new buildings and development of a large regional health system, while forging relationships with state government that yielded significant increases in capital support. During Paz’s tenure, Penn State also established an institute funded by a National Institutes of Health Clinical and Translational Science Award – the same NIH program that has funded Ohio State’s Center for Clinical and Translational Science since 2008.

Prior to his tenure at Penn State, Paz served as dean of the Robert Wood Johnson Medical School and CEO of the Robert Wood Johnson University Medical Group from 1995 to 2006. (Robert Wood Johnson formally integrated into Rutgers University in 2013.) Under Paz’s leadership, NIH funding increased by more than 88 percent, and the endowment increased by over 600 percent.

Nationally, Paz has served as a board member and chair of the Association of Academic Health Centers (AAHC) and of the Association of American Medical Colleges’ (AAMC) Council of Deans.

Paz is board certified in internal medicine and pulmonary medicine. He completed his internal medicine residency at Northwestern University and a postdoctoral fellowship in pulmonary and critical care medicine and environmental health sciences at Johns Hopkins University. Early in his career, he held faculty and administrative appointments at Hahnemann University School of Medicine (now Drexel University College of Medicine) in Philadelphia. He earned a bachelor’s in biology and psychology and his medical degree from the University of Rochester, and a master’s in life science engineering from Tufts University.

Study in mice suggests that when fathers exercise, their offspring are healthier

Wed, 24 Oct 2018 17:26:00 -0400

A new study in animals suggests that paternal exercise might have significant impact on the health of offspring – even into adulthood.

Researchers used a mouse model to investigate how a father’s exercise regimen would affect his offspring’s metabolic health.

They fed male mice either a normal diet or a high-fat diet for three weeks. Some mice from each diet group were sedentary and some exercised freely. After three weeks, the mice bred and their offspring ate a normal diet under sedentary conditions for a year.

The researchers reported on Oct. 22 in the journal Diabetes that adult offspring from sires who exercised had improved glucose metabolism, decreased body weight and a decreased fat mass.

“Here’s what’s really interesting: Offspring from the dads fed a high-fat diet fared worse, so they were more glucose intolerant. But exercise negated that effect,” said study leader Kristin Stanford, a physiology and cell biology researcher with The Ohio State University College of Medicine at the Wexner Medical Center.

“When the dad exercised, even on a high-fat diet, we saw improved metabolic health in their adult offspring.”

Laurie Goodyear of the Joslin Diabetes Center and Harvard Medical School co-led the study.

“This work is an important step in learning about metabolic disease and prevention at the cellular level,” said Dr. K. Craig Kent, dean of the Ohio State College of Medicine.

Recent studies have linked development of type 2 diabetes and impaired metabolic health to the parents’ poor diet, and there is increasing evidence that fathers play an important role in obesity and metabolic programming of their offspring.

In this new work, Stanford’s team also found that exercise caused changes in the genetic expression of the father’s sperm that suppress poor dietary effects and transfer to the offspring.

“We saw a strong change in their small-RNA profile. Now we want to see exactly which small-RNAs are responsible for these metabolic improvements, where it’s happening in the offspring and why,” said Stanford, a member of Ohio State’s Diabetes and Metabolism Research Center.

Previous studies from this group have shown that when mouse mothers exercise, their offspring also have beneficial effects of metabolism.

“There’s potential for this to translate to humans. We know that in adult men obesity impairs testosterone levels, sperm number and motility, and it decreases the number of live births,” Stanford said. “If we ask someone who’s getting ready to have a child to exercise moderately, even for a month before conception, that could have a strong effect on the health of their sperm and the long-term metabolic health of their children.”

(Video via ABC6/Courtesy: CNN Newsource)

The researchers believe the results support the hypothesis that small RNAs could help transmit parental environmental information to the next generation.

“Based on both studies, we’re now determining if both parents exercising has even greater effects to improve metabolism and overall health of offspring. If translated to humans, this would be hugely important for the health of the next generation,” Goodyear said.

Other Ohio State researchers involved in the study were Lisa Baer, Adam Lehnig and Joseph White.

Funding from the National Institutes of Health supported this research.