A research team has unveiled a crucial mechanism that helps regulate DNA damage repair, with important implications for improving cancer treatment outcomes.

The result was published in Cell Death & Differentiation. The team was led by Professor Zhao Guoping at the Hefei Institutes of Physical Science of the Chinese Academy of Sciences.

The efficacy of radiotherapy is largely limited by the DNA damage repair capacity of tumor cells. When ionizing radiation induces DNA double-strand breaks—the primary lethal damage—tumor cells often exhibit abnormal overexpression of DNA repair proteins, establishing a robust damage response system that drives clinical radioresistance. To address this challenge, the team deciphered the regulatory network of epigenetic modifications in DNA damage repair.

Most cells in the human body each contain about six feet of DNA. Yet the nucleus, where DNA is coiled, is no larger than a single speck of dust. Despite its density, DNA is not a tangled ball of yarn. It is organized into intricate layers of loops that fold and unfold in response to cues from the cell.

Scientists know that the three-dimensional shape of DNA is important. This long helical thread is peppered with genes that are translated into proteins to drive cellular activity. And the structure of the genome —those layers of loops—determines which genes are active at any given time.

How the three-dimensional structure of the genome is maintained, however, is less clear. Structural changes and abnormalities are associated with many diseases, such as cancer and developmental disorders. Identifying what controls genome structure could yield targets for treatment.

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C to be a key factor for B-cell ALL (B-ALL) development and maintenance. While cyclin C is not essential for normal hematopoiesis, CcncΔ/Δ BCR::ABL1 + B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ BCR::ABL1 + cells resulting in the inability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as a potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.

The Philadelphia (Ph) chromosome, a product of the reciprocal translocation t(9;22)(q34;q11) between chromosomes 9 and 22, encodes the BCR::ABL1 fusion oncoprotein.¹ The constitutively active BCR::ABL1 tyrosine kinase is a hallmark of chronic myeloid leukemia (CML) and drives a subset of acute lymphoblastic leukemia (ALL). The incidence of Ph positive (Ph⁺) ALL correlates with age, from only 3% in pediatric ALL to around 25% in older adults.² Direct targeting of the BCR::ABL1 kinase with tyrosine kinase inhibitors (TKI) has been a breakthrough in targeted cancer therapy. Despite efforts to counteract TKI resistance and improve safety profiles, refractory BCR::ABL1⁺ leukemia, as well as toxicities and long-term side effects of TKI, present particular therapeutic challenges.^3–5

The clinical relevance of cyclins and their associated cyclin-dependent kinases (CDK) has been a major focus of research for several years. Cyclin-CDK complexes do not only drive the cell cycle, but are also important players in various other cellular processes including transcriptional and epigenetic regulation, metabolism or stem cell self-renewal.⁶ In line with their importance in different pathways, cyclin-CDK complex dysregulation is implicated in many different types of cancer.⁷