Dr. Cheng-Fu Kao, an Associate Research Fellow in the Institute of Cellular and Organismic Biology (ICOB), has provided new insights to the role of histone H2B mono-ubiquitylation (H2Bub) that contributes to DNA damage bypass through fine tuning chromatin structure for the efficiently bypass of DNA damage. This study also provides new insights to the role of chromatin structure in genome stability and diseases in the future. The research was published in Proceedings of the National Academy of Sciences of the United States of America (PNAS) on March 14th, 2017.
　　DNA lesion bypass is mediated by DNA damage tolerance (DDT) pathways and homologous recombination (HR). The DDT pathways involve translesion synthesis (TLS) and template switching (TS). DNA damage bypass is crucial for precluding mutations and DNA double-strand break, therefore plays an important role in cancer prevention. However, it is unclear how these processes are coordinated within the context of chromatin. Here we show that, an ubiquitin ligase specific for histone H2B, Bre1 is recruited to chromatin in a manner coupled to replication of damaged DNA. In the absence of Bre1 or H2Bub, cells exhibit accumulation of unrepaired DNA lesions. Consequently, the damaged forks become unstable and resistant to repair. Dr. Kao’s team provides physical, genetic and cytological evidence that H2Bub contributes toward both TS as well as HR. Using an inducible system of DNA damage bypass, they further show that H2Bub is required for the regulation of DDT after genome duplication. They propose that Bre1-H2Bub facilitates fork recovery and gap-filling repair by controlling chromatin dynamics in response to replicative DNA damage.
　　This research was carried out by the team of Dr. Kao in ICOB and collaborated with Dr. Helle D. Ulrich in Institute of Molecular Biology (IMB), Germany (https://www.imb.de/). Dr. Kao received a short-term fellowship funded by The European Molecular Biology Organization (EMBO) to visit Dr. Ulrich’s laboratory in January, 2016. The primary author, Shih-Hsun Hung, is a PhD candidate of National Defense Medical Center in Taiwan who performed the majority of experiments and Dr. Ronald P. Wong, a postdoctoral fellow in Dr. Helle D. Ulrich’s laboratory, also contributed to some of the experiments. The artwork is created by Mr. Shan-Chi Hsieh, a research assistant in Kao’s laboratory.
The research project was funded by grants from Academia Sinica and the Ministry of Science and Technology of Taiwan. The full research article can be reached at the following link: http://www.pnas.org/content/114/11/E2205.long