『Cover Story』Unveiling the new guardian of DNA replication!

Volume 85, Issue 3

Zhanzhan Xu1,4 ∙ Chen Nie1,4 ∙ Junwei Liao1 ∙ Yujie Ma1 ∙ Xiao Albert Zhou1 ∙ Xiaoman Li1 ∙ Shiwei Li1 ∙ Haodong Lin1 ∙ Yefei Luo1 ∙ Kaiqi Cheng1 ∙ Zuchao Mao1 ∙ Lei Zhang1 ∙ Yichen Pan1 ∙ Yuke Chen2 ∙ Weibin Wang1 weibinwang@bjmu.edu.cn ∙ Jiadong Wang1,3,5 

The cover of this issue of Molecular Cell is “DDX39A resolves replication fork-associated RNA-DNA hybrids to balance fork protection and cleavage for genomic stability maintenance” published by Professor Wang Jiadong and Associate Researcher Wang Weibin of Peking University.

Research background

During DNA replication, ensuring the stability of replication forks in transcriptionally active regions is essential for accurate replication and preventing mutations. Replication forks are two Y-shaped structures that unwind the double helix and advance in both directions during DNA replication. In transcriptionally active regions, a complex molecular environment may be generated due to the simultaneous activity of RNA polymerase and DNA polymerase, which poses a challenge to the stability of replication forks. The background of this study is based on the scientific question of how to maintain the stability of replication forks in transcriptionally active regions to prevent DNA damage and mutations.

Research significance

This study first discovered ubiquitous replication fork-associated RNA-DNA hybrids (RF-RDs) in transcriptionally active regions of human cells. These hybrids act as a protective barrier that prevents DNA2-mediated nascent DNA degradation and replication fork collapse under replication stress. This discovery reveals a new function of RNA-DNA interactions in maintaining replication fork stability. The study also identified DDX39A as a RAD51-associated protein that binds to stalled replication forks and resolves RF-RDs, thereby promoting DNA2-mediated DNA resection and replication fork restart. This discovery provides a new perspective for understanding replication fork restart and DNA damage repair.

The study also showed that excessive dissolution of RF-RDs can lead to replication fork collapse and genomic instability, while insufficient dissolution of RF-RDs under replication stress increases replication fork stability and leads to chemotherapy resistance. This finding emphasizes the balancing role of RF-RDs in maintaining replication fork stability and chemotherapy sensitivity.

Research Outlook

Based on the key role of RF-RDs in maintaining replication fork stability and chemotherapy sensitivity, future studies can explore targeting RF-RDs as a new strategy to enhance the efficacy of chemotherapy. By regulating the formation and dissolution of RF-RDs, it may be possible to improve the response of some cancer patients to chemotherapy drugs. Although this study revealed the role of RF-RDs and DDX39A in replication fork stability, there are still many unsolved mysteries. For example, the specific formation mechanism of RF-RDs, how DDX39A recognizes and binds to stalled replication forks, and the interaction between RF-RDs and other DNA repair pathways are all important directions for future research.

In order to study RF-RDs and replication fork stability more deeply, new tools and technologies need to be developed to monitor the formation, dynamic changes, and interaction of RF-RDs with replication forks in real time. These tools and techniques will help reveal more details about the mechanisms of DNA replication and repair.

Cover Design Process

• • The cover design is closely centered around the theme of the paper, namely, "DDX39A resolves replication fork-associated RNA-DNA hybrids to balance replication fork protection and cleavage to maintain genome stability". The Songdi design team intuitively displays the key findings in the paper through a clever combination of images and text. The center of the cover is an enlarged replication fork structure, highlighting the focus of the research. At the same time, through the changes in color and shape, as well as the description of the text, complex information such as replication fork stability, RNA-DNA hybrids, and the role of DDX39A protein in it is conveyed.
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  • The color matching of the cover is both professional and visually impactful. Two tones of blue and white are mainly used. Blue is usually associated with concepts such as science, technology, innovation, and trust, which is very suitable for the cover design of scientific journals. White provides clarity and readability, making the text and information on the cover more prominent. In addition, other colors are used on the cover to embellish and enhance the visual effect, such as yellow and red in the replication fork structure, and light gray in the background.
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  • The style of the cover is simple and modern, in line with the professional image of scientific journals. The complex structure of the replication fork and the existence of RNA-DNA hybrids are displayed through fine lines and clear images. At the same time, the layout of the cover also reflects professionalism and readability. The text size, font and spacing are carefully designed to ensure that readers can read and understand easily. In the end, the cover was highly recognized by the teacher and the journal editor and was successfully published!