Transcription helper plays a decisive role in DNA repair

Scientists led by Randolph Caldwell and Prof. Dr. Horst Zitzelsberger from the Research Unit Radiation Cytogenetics have carefully investigated the activity of Positive Coactivator 4 (PC4). Their findings, as published in 'Scientific Reports', indicate that PC4 plays a crucial role in the response to DNA damage and repair outcome. It could consequently be an interesting target for cancer research and radiotherapy.

The PC4 molecule binds single-strand DNA and is a part of the enzyme complex involved with RNA polymerase II, which reads the genes and transcribes them into mRNA. Together with colleagues from the Bundeswehrinstitut für Strahlenbiologie [German Armed Forces Institute of Radiation Biology] at Ulm University, the Helmholtz researchers were able to demonstrate that PC4 has a previously unknown function at its N-terminus that appears to also be involved in the repair of DNA damage.

They chose the DT40 chicken B cell line as the object of their study, which provides several advantages: it reliably allows individual genes, PC4 in this case, to be selectively knocked-out. Additionally, it is well-suited for studies on DNA repair due to the cell’s lack of the protein p53, which itself is involved in repair processes and could mask PC4’s true role in repair. DT40 also has the advantage of defined locus-specific DNA damage of its immunoglobulin genes that allows the study of different repair paths.  

The scientists discovered that the previously unknown activity at the PC4 N-terminus can influence which pathway is taken for the DNA repair response and subsequent repair outcome. Two pathways are very significant here: base excision repair (BER) and homologous recombination (HR). "Our data suggest that PC4 plays a role in influencing the so-called short-patch/long-patch aspect of BER.  In areas of clustered lesions, an increase in repair-induced resected DNA could lead to double strand breaks, thereby shifting the dynamics of repair to HR or 'nonhomologous end joining' (NHEJ)," first author Caldwell summarizes.

In the future, the researchers want to clarify the mechanistic background of PC4's newly discovered N-terminus function and investigate if PC4 is also suitable as a therapeutic target structure for cancerous diseases and radiotherapy.

Further information:

Scientific publication: Caldwell, RB. et al. (2016). Positive Cofactor 4 (PC4) is critical for DNA repair pathway re-routing in DT40 cells, Scientific Reports, DOI:10.1038/srep28890. Link to the publication...

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The Research Unit Radiation Cytogenetics (ZYTO) investigates radiation-induced chromosome and DNA damage in cell systems and human tumours. The focus is on clarifying the mechanisms associated with radiation-induced carcinogenesis and radiation sensitivity of tumour cells. The aim of this research is to find biomarkers associated with radiation-induced tumours in order to develop personalized radiation therapy for the stratification of patients. ZYTO is a part of the Department of Radiation Sciences (DRS).

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Transcription helper plays a decisive role in DNA repair