Grant Funds DNA Replication Research, Diversity Program

Surtees, professor of biochemistry and associate dean of undergraduate education and STEM outreach in the Jacobs School of Medicine and Biomedical Sciences, is principal investigator on a five-year, $2.45 million R01 grant from the National Institute of General Medical Sciences.

The grant will fund exploration of DNA replication and target therapeutic pathways for cancer treatment, along with establishing a community lab for local students to get hands-on research experience at the Jacobs School.  

Surtees’ grant relates to the NIH’s recently launched Research With Activities Related to Diversity (ReWARD) program, which supports both scientific research and efforts to enhance diversity in the biomedical research workforce. 

In terms of basic research, many questions about DNA replication remain, Surtees says. Dividing cells seek to create exact copies of their DNA, which is made up of nucleotide building blocks called dNTPs. During cell division, dNTP pools must contain both the right nucleotides and the right amounts for error-free replication. “There are multiple mechanisms in place to ensure that replication fidelity is high,” Surtees says.

Having too many dNTPs can cause DNA replication errors and mutations. “Having elevated dNTP pools elevates your mutation rate, which in turn can lead to a predisposition to cancer,” Surtees says. Because cancer cells divide so frequently, they typically contain elevated dNTP pools, which could also prompt them to evolve and potentially evade therapies.

Using a yeast model and genetic screening, Surtees and her colleagues have identified potential target pathways in cells with altered and elevated dNTP pools. Knocking out these pathways in combination with altered dNTP pools inhibits cell growth. Now, she’s trying to figure out exactly how and why this growth inhibition occurs.

“Why does knocking out that pathway compromise cellular fitness? And does that pathway sensitize the cells to chemotherapeutic agents?” she asks, noting that knocking out specific pathways could make certain cancer therapies more effective or even reduce treatment side effects.

Surtees has also been exploring disabling cells’ mismatch repair system, or MMR, which acts like a spell-check to spot replication errors. “When we knock out [MMR] in combination with altered dNTP pools, we see a significant decrease in cell viability. The cells don’t grow very well at all,” she says, indicating that a high mutation rate could be killing the cells.

On the other hand, it’s possible that knocking out MMR is affecting the DNA damage checkpoint response, Surtees says — which cells use to detect and repair damage — opening potential new therapeutic targets if so.

The grant will advance these investigations while illuminating the basic biology behind these effects. “It’s important to not only understand what pathways might be involved in compromising fitness, but it really is important to understand how,” Surtees says. “Once we have that fundamental understanding, we’re better able to develop rational treatments.”

In addition to research on the cellular level, the grant supports research on the community level as well. As co-director of the Genome, Environment and Microbiome Community of Excellence, or GEM, Surtees has had significant community engagement experience promoting genome and microbiome literacy and K-12 student outreach through development of hands-on engagement. Co-investigator on the current grant, Sandra Small, PhD, was the GEM education manager and remains dedicated to bringing science into K-12 classrooms.

Now, the new grant will establish the Community Education Laboratory in Life Sciences, or CELLS, at the Jacobs School to involve students who are underrepresented in the biomedical workforce with authentic scientific research experiences. CELLS will bring Buffalo students from various grade levels to the Jacobs School to help conduct real research amid actual lab space.

“Our goal is to expose students to the possibility of research and to bring in students who are really excited about exploring the world around them through actual hands-on work,” Surtees says.

Surtees describes herself as an “accidental scientist” who was exposed to opportunities that inspired her career in science — but many individuals don’t have those same exposures. “There are a lot of people who don’t have those opportunities put in front of them. As a result, a lot of students are unaware of this path or don’t see themselves as potentially part of this enterprise,” she says. “Without these diverse perspectives, we’re missing out on a lot of intellectual capital.”

In addition to raising awareness of scientific career possibilities, the program, which will include a community advisory board, hopes to create an ecosystem of support and sense of belonging that are needed to nurture and retain underrepresented students in the sciences, Surtees says.

Surtees and Small have a strong partnership with the Research Laboratory High School for Bioinformatics and Life Sciences, part of Buffalo Public Schools. Students from this school will comprise the first trainee cohort in the program. Then, potentially other school students and undergraduates can be involved, along with graduate student mentor trainees and additional Jacobs School researchers and labs, as the program matures. 

Surtees further hopes that welcoming young researchers will by extension allow their families and communities to feel more included within academic research and will help foster the Jacobs School being “the community’s medical school.”