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Molecular Biology Group

Molecular Biology Group

Functional Analysis of the Multifunctional Protein Praja1

Overview

In the Molecular Biology Group, we conduct research aimed at understanding life at the molecular level through the functional analysis of proteins, the cellular workers. Currently, our focus is on a protein called Praja1, possessing two distinct molecular functions.

Praja1 functions both as an “E3 ubiquitin ligase,” which recognizes and directs the degradation of unwanted proteins, and as a “DNA-protective protein” that safeguards nuclear DNA from damage. Our research comprehensively examines both of these aspects.

Overview of the two molecular functions of Praja1

Praja1 as an “E3 ubiquitin ligase”

Protein expression in living organisms is strictly regulated in terms of when, where, and how much is expressed. Among the enzymes involved in this process, E3 ubiquitin ligases (E3 enzymes) are known to direct the degradation of proteins that are no longer needed. Inadequate E3 enzyme activity is thought to lead to the accumulation of toxic protein waste, which in turn links to disease onset and aging.

Since Praja1 broadly recognizes and degrades aggregating proteins commonly found in neurodegenerative diseases (such as α-synuclein, TDP-43, and FUS), it is suggested to play a suppressive role in the onset and progression of these diseases. Our research has revealed that Praja1 also recognizes and degrades Tau protein, which aggregates in neurodegenerative diseases such as Alzheimer’s disease1. We are currently exploring the interaction between Praja1 and Tau in greater depth. Additionally, collaborating with the electrochemistry group within our laboratory, we are developing biosensors utilizing Praja12.

Praja1 as a “DNA-protective protein”

Intracellular DNA is damaged daily by various factors. In addition to internal factors such as reactive oxygen species generated by metabolic activity within the body, it is also exposed to external factors such as ultraviolet radiation and radiation therapy for cancer. Furthermore, the cosmic rays that humans are exposed to during space travel can damage DNA, which will pose a challenge in the future as humanity seeks to improve its quality of life in space (space QOL).

Through molecular evolutionary analysis, we discovered that Praja1 acquired the ability to localize to the cell nucleus during the evolution of mammals3. Furthermore, while investigating the physiological role of Praja1 after its entry into the nucleus, we obtained a novel finding—previously unreported—that Praja1 protects DNA4. We are currently working to elucidate the molecular mechanisms by which Praja1 exerts its DNA-protective effects.

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