A new grant allows researchers to explore oddities in the waning moments of the cell cycle, with implications for cancer therapies and Fanconi anemia research.
Cells grow, duplicate and divide in a process known as the cell cycle. A new National Institute of Health (NIH) grant will allow U of M researchers — led by Naoko Shima, an associate professor in Genetics, Cell Biology, and Development — to study an unusual aspect of the cycle. Implications include development of cancer therapies and research on a rare and fatal disease, Fanconi anemia.
Shima is exploring these questions alongside two co-investigators, Associate Professor Alex Sobeck and Professor Anja Bielinsky, and is recruiting a new PhD student and postdoctoral scholar. The incoming researchers will join Emma Traband, a technician, and Anika Tella, an undergraduate student, in the Shima lab.
If the cell cycle consisted of a 24-hour hour period, in normal conditions, DNA would duplicate between 10 a.m and 6 p.m. Known as the S phase, it’s etched into every cell cycle schematic and taught in every introductory biology course. However, a few years ago, scientists reported that in human and mouse cells, DNA can replicate well past the normal DNA replication window, just before cells divide. This process is known as mitotic DNA synthesis (MiDAS). Shima and colleagues study what molecules control it, as MiDAS occurs when cells attempt to cope with stressful conditions.
“I don’t mention my research topic in my introductory genetics course because it goes against the cell cycle we teach students. It can get really confusing,” says Shima. “When a student asks though, I’m always excited to share. Understanding how stress can alter ‘normal’ biologic processes is fascinating.”
Recently, Shima and colleagues found a key difference in how cells regulated MiDAS in cancerous cells and normal cells. Understanding how these two molecules — known as RAD52 and FANCD2 — regulate MiDAS in cancer cells is central to this research. Turning these molecules “on” and “off” in healthy and cancerous cells allow researchers to tease out their roles.
“We discovered that RAD52-driven MiDAS is seen only in cancer cells. We tested so many times in so many ways, but this molecule doesn’t do anything in normal human cells. You take out RAD52, nothing changes in MiDAS in normal cells,” says Shima.
However, when researchers inhibit RAD52, MiDAS is impaired in cancer cells. In normal cells, MiDAS is regulated by FANCD2, a protein mutated in Fanconi anemia. Cancer cells find a better way to cope with stress to invent a secondary MiDAS mechanism by exploiting RAD52 on top of the FANCD2-driven MiDAS. This finding is important in the development of cancer therapies, something that Shima has explored. If researchers inhibit RAD52, and thus MiDAS, normal cells won’t be affected, but cancerous cells will be unable to complete DNA replication and die off.
Shima also discovered that the fundamental form of MiDAS is regulated by FANCD2, a key protein mutated in Fanconi anemia.
The research will help illuminate a mystery — why mice are a poor model system to understand Fanconi anemia, a rare genetic disease. Mice are commonly used to study human diseases as we share many genetic features with them, but for Fanconi anemia, mice weren’t showing characteristics of the disease. For years, this disconnect baffled scientists.
Shima found recently that MiDAS is regulated in a different way in humans and mice. “Since we are slowly disentangling the differences, we plan to use this information to make a better mouse model to study Fanconi anemia,” says Shima.