UM Researchers Co-develop First Method to Map Most Common DNA Lesions

A team of Miller School researchers and an international group of collaborators have developed a novel method of mapping the locations of the most common DNA lesions. Their findings have implications for a better understanding of the mechanisms of both aging and cancer.

Claes Wahlestedt, M.D., Ph.D., professor of psychiatry and behavioral sciences and associate dean for therapeutic innovation at the University of Miami Miller School, and Philipp Kapranov, Ph.D., professor and director of the Institute of Genomics in the College of Biomedical Sciences at Huaqiao University in Xiamen, China, and are co-senior authors of a new study, “Novel Approach Reveals Genomic Landscapes of Single-strand DNA Breaks with Nucleotide Resolution in Human Cells,” published December 20 in Nature Communications. Natalie Ricciardi, a Ph.D. candidate in the Miller School’s Department of Biochemistry and Molecular Biology, is one of the co-authors.

“Our DNA can be viewed as a hard drive that stores a multitude of molecular programs that make us who we are and ensure that our bodies function properly,” Dr. Wahlestedt said. “This enterprise-grade hard drive functions every second of every day in every cell of our body. However, just as hard drives in computers get damaged, DNA gets constantly damaged, too — either by natural processes of copying or reading the programs stored there, or by environmental factors such as UV rays and toxins.”

DNA damage, he noted, has long been known to be associated with some of the most basic health problems facing humankind, notably aging, cancer and neurodegeneration.

The DNA of most living things, including humans, is made of two very long molecules — strands — bound to each other. Each strand contains genetic information, and therefore integrity of both strands is critical. However, DNA can and does break on both or just one strand. Single-strand breaks represent what is thought to be the most common type of damage to DNA. Until now, however, there was no technique capable of precisely measuring all these breaks at once. The researchers developed an entirely new method to map such types of DNA lesions — SSiNGLe, for single-strand break mapping at nucleotide genome level — and applied it to various human cell types.

“To our surprise, we found that the breaks are not distributed randomly, but rather favor certain sectors of the drive that control readouts of specific programs or store the programs,” Dr. Wahlestedt said. “Moreover, during stressful conditions, the numbers of breaks increase in those specific locations.”

“It’s too early to say what the meaning of specific locations of breaks in different parts of the DNA hard drive is,” Dr. Kapranov said. “Perhaps these regions break more easily or perhaps they need to break for the programs to be read out. Nonetheless, the study opens a door into a totally new field.”

Furthermore, breaks seem to favor places where genetic changes tend to occur, suggesting that the erroneous repair of these breaks might lead to mutations that could contribute to diseases, and even potentially to evolution if they occur in germline cells. This provocative observation potentially has far-reaching implications. If breaks favor the certain parts of DNA and those breaks increase under stress, it also might mean that stress could influence where the DNA changes occur, too.

“This could be quite relevant to anti-cancer therapies, since this study shows that treatments with these drugs could dramatically change the patterns of breaks in DNA, thus potentially causing mutations in both cancerous and healthy cells of patients,” Dr. Wahlestedt said.

Last but not least, the authors have shown that these singled-stranded DNA breaks change with age. Interestingly, the locations of the breaks were shown to correlate with chronological age.

“These breaks are most definitely telling us something new about the aging process,” Dr. Wahlestedt said. “Notably, we found more age-related breaks in certain parts of the genome. We feel that this new method can have broad utility in human aging research.”

Tags: DNA lesions, genome breaks, human aging research, single-stranded DNA breaks, SSiNGLe