Is Damage and Repair of DNA Required for Differentiation?

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A finding that HL60 cells when exposed to ultraviolet light (UV) underwent terminal differentiation has led to a question that does transient formation of single stranded brakes (SSB) in nuclear DNA as T-T dimers formed by UV are repaired induced the cell differentiation? Hence, we examined the validity of hypothesis that "Formation of SSB in DNA and their repair is required for cell differentiation and aging". A series of experiments were carried out using peripheral lymphocytes. To carry out the experiments, an in situ nick translation method was developed in order to localize SSB histochemically in each cell nuclei. When peripheral lymphocytes were exposed to UV, SSB was formed about 2 hours after the UV irradiation and the SSB gradually decreased thereafter. The T-T dimers were most frequent immediately after the irradiation and gradually decreased. These findings together with the previous finding that when the lymphocytes were exposed to UV, the lymphocytes produced a series of proteins which appear when the cells were stimulated with mitogen suggested that the SSB formation and their repair are associated with the cell differentiation. To examine whether the phenomenon also takes place in in vivo, ears of mice were exposed to UV and studies similar to that done on the lymphocytes were carried out. It was found that the basal cells in epidermis has an ability to repair SSB whereas cells in prickle cell layers has lost the ability. In the basal cells, there were pre-existed SSB and newly formed SSB. The former are inaccessible to DNA polymerase and only the latter were repaired. These finding suggested that in a given nuclei there are two domains, one where SSB are repaired and transcription from DNA to hnRNA takes place and another where SSB remains and no transcription takes place.