Platinum-based chemotherapy drugs like cisplatin and oxaliplatin are often used to treat a variety of cancers such as breast, lung, colon, and brain cancer. These drugs work by damaging DNA inside cancer cells, which stops the cells from dividing and spreading. However, cancer cells can become resistant to these drugs over time, making treatment less effective. Understanding how these drugs interact with DNA is crucial for uncovering the roots of resistance and finding ways to overcome it.

Now, a study led by 4D Nucleome researcher Dr. Frank Alber at the University of California Los Angeles sheds light on how the 3D organization of DNA inside the cell nucleus affects its vulnerability to platinum-based drugs. While previous research shows that not all DNA segments are equally susceptible to damage, this is the first study to investigate this phenomenon in living cells.

Using 3D genome models and human cancer cells, the researchers found that DNA that was closer to the center of the nucleus, often where the most active genes are located, was more susceptible to cisplatin-induced damage than DNA located toward the edge of the nucleus. The group also discovered that DNA located near certain structures inside the nucleus – called “nuclear speckles” – was more susceptible to cisplatin-induced damage than DNA that was located further from a nuclear speckle. They observed these findings regardless of the activity of the genes coded in the DNA.

Their results reveal that DNA organization inside the nucleus has a unique and relevant effect on susceptibility of DNA to damage induced by platinum-based chemotherapeutics. Some regions are more vulnerable to damage, while others are protected. These effects may have important implications for the performance of cisplatin and other platinum-based chemotherapeutics in treating cancer. Knowing more about how platinum-based drugs interact with our DNA may help us understand how we can overcome chemoresistance and ultimately improve cancer treatment. 

Reference

Wang Y, Yildirim A, Boninsegna L, Christian V, Kang SL, Zhou XJ, Alber F. 3D genome organization shapes DNA damage susceptibility to platinum-based drugs. Nucleic Acids Res. 2025 May 22;53(10):gkaf315. doi: 10.1093/nar/gkaf315.