Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States

Abstract

DNA double strand breaks (DSBs) are known to be the most toxic and threatening of the various types of breaks that may occur to the DNA. However, growing evidence continuously sheds light on the regulatory roles of programmed DSBs. Emerging studies demonstrate the roles of DSBs in processes such as T and B cell development, meiosis, transcription and replication. A significant recent progress in the last few years has contributed to our advanced knowledge regarding the functions of DSBs is the development of many next generation sequencing (NGS) methods, which have considerably advanced our capabilities. Other studies have focused on the implications of programmed DSBs on chromosomal aberrations and tumorigenesis. This review aims to summarize what is known about DNA damage in its physiological context. In addition, we will examine the advancements of the past several years, which have made an impact on the study of genome landscape and its organization.

The Potentiation of Anti-Tumor Immunity by Tumor Abolition with Alpha Particles, Protons, or Carbon Ion Radiation and Its Enforcement by Combination with Immunoadjuvants or Inhibitors of Immune Suppressor Cells and Checkpoint Molecules

“…Radiation induces several cell damage responses, including apoptotic cell death, mitotic catastrophe, necroptosis, ferroptosis, and senescence [ 10 ], some of them initiated by DNA double strand breaks (DSBs), which are known to be the most toxic and threatening of the various types of breaks that may occur to the DNA [ 11 ].…”

DNA damage and repair in differentiation of stem cells and cells of connective cell lineages: A trigger or a complication?

“…66 Role of the DNA strand breaks in lymphocyte differentiation merits a separate analysis and the topic has been recently reviewed in detail. 5,6 Conclusions PSC, including ESC and iPSC, are rapidly dividing cells with highly active DDR mechanisms to ensure the stability and integrity of DNA. In PSCs, the most common DDR mechanism is error-free HR that is primarily active during the S phase of the cell cycle, whereas in quiescent, slow-dividing, or non-dividing tissue progenitors and terminally differentiated cells, error-prone NHEJ mechanism of DSB repair is dominating.…”

“…We have summarized the literature on the role of DNA breaks in differentiation more than a decennium ago. 3 Ever since the importance of DNA breaks in the function of neurons, 4 immune response, 5 , 6 and spermatogenesis 6 has been confirmed several times and mechanisms of the DNA breakage have been elucidated. During meiosis, the double-strand breaks (DSB) are induced by the SPO11 enzyme, whereas the DSBs for V(D)J recombination are induced by the RAG and repaired via a non-homologous end-joining mechanism (NHEJ).…”

“…The process of the B-cell receptor diversification is initiated by the Activation-Induced Cytidine- Deaminase (AID). 6 DNA breakage triggers also muscle cell differentiation, in this case, breaks are induced by the caspase-activated DNase, an enzyme that is mostly involved in the process of apoptosis. The DNA breaks were mapped in the promoter of the p21 gene.…”

“… 12 For instance, spermatogenesis-related DSB were localized by applying this approach. 6 , 13 , 14 The DNA breaks involved in a V(D)J recombination and induced by a RAG were mapped also using the next generation sequencing. 15 In the present review we aimed to summarize the latest literature data on the role of DNA strand breaks in the pluripotent stem cell and connective tissue stem cell proliferation and differentiation.…”