New Brunswick, N.J. – Research by Rutgers Cancer Institute of New Jersey investigators and others shows that the architecture of a cell’s nucleus influences the type and frequency of mutations in cancer genomes beyond the effects already captured by DNA packaging and ordering. Rutgers Cancer Institute resident research member Subhajyoti De, PhD, who is an assistant professor of pathology at Rutgers Robert Wood Johnson Medical School, is the senior author of the work published in the October 2, 2017, online issue of Nature Structural & Molecular Biology (doi: 10.1038/nsmb.3474). Dr. De, who is also a member of the Cancer Institute’s Genomic Instability and Cancer Genetics Program, shares more about the work.
Q: Why is this topic important to explore?
A: Genomic DNA, which is about 2 meters long, is intricately packaged inside a cell’s nucleus, which is much smaller than the width of a human hair, in a complex manner. Nuclear packaging of DNA can vary a bit between cell types, but some genomic regions are always located in the nuclear core while others are closer to the nuclear periphery. It is unclear whether such an arrangement affects DNA damage and repair differently between regions that are closer to the nuclear periphery and those that are at the core. Answers to this question are important to determine aspects of how genetic changes – called mutations – occur in cancer, and consequences of radiation or certain types of chemotherapy in cancer patients.
Q: How was this study structured and what did you learn?
A: We analyzed genome-wide somatic mutations from more than 350 tumors of six major cancer types from skin, lung, stomach, blood, and prostate. Ours was one of the early studies to investigate mutation patterns in cancers in the context of their 3D localization in the nucleus. We found that both the burden of mutations and the types of mutations differ between nuclear core and periphery, in a manner that was broadly similar between these cancer types of different origin. For instance, certain patterns of smoking and UV-related signatures in lung and skin, respectively, were more common in the nuclear periphery. Our findings indicated that different DNA damage and repair mechanisms might be operative depending on nuclear localization.
Q: What is the implication of these findings and potential applications to future cancer treatment and other diseases?
A: Our results are important for understanding the biology of cancer, and have implications for improving treatment. They indicate that different DNA damage and repair processes might be active at the nuclear core and periphery, such that factors such as smoking and UV light damage DNA differently in different genomic regions. In a similar manner, effects of radiation and chemotherapy, which systematically damage DNA in cancer cells during treatment, may be manifested in the genome a nuclear localization-dependent manner. Our findings have the potential to identify novel DNA repair mechanisms and genes therein, which could be targeted in cancer.
Along with Dr. De, the other authors on the research are his graduate student Kyle S. Smith; Shridar Ganesan of Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School; and Lin L. Liu and Franziska Michor of Dana-Farber Cancer Institute.
This work was supported in part by the National Institutes of Health (NIH): T15LM009451to KS, U54CA193461to FM and a Cancer Center Support Grant (P30CA072720); as well as the American Cancer Society and the Boettcher Foundation to SD.