38 | Chapter 2 of gH2AX, carboxy-terminal binding protein (CtBP)-interacting protein (CtIP) endonuclease takes over the hairpin opening and processing activities. Though CtIP can open the hairpin, in G1-phase lymphocytes the CtIP-generated joints are not efficiently processed by NHEJ. CtIP uses microhomologies to process the joints, which results in frequent chromosomal deletions. Thus, the DSBs-recruited gH2AX ensures the maintenance of genomic integrity in the G1 phase192. Figure 4. Schematic depiction of B-cell-specific regulatory processes impinging on RAG expression triggered by the formation of DSBs. The formation of DSBs leads to autophosphorylation of the DNA damage sensor Ataxia-telangiectasia mutated (ATM). The activation of ATM triggers several negative feedback mechanisms that limit the expression of RAG1 and RAG2, such as the inhibition of FOXO1 and FOXP1 transcription factors either directly or through downstream intermediates. The ATM-driven stabilization of p53 drives the expression of miR-34a, which is a negative regulator of FOXP1. Next to the effect of DSBs on RAG expression, the activated ATM also triggers the DNA damage response, activates cell-cycle arrest, and, depending on the extent of the DNA damage, the pro-apoptotic or the pro-survival and differentiation signals. Created with BioRender.com RAG: driver of lymphoid malignancies Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in developed countries, accounting for 81% of childhood leukemias and one-third of all cancers diagnosed in children of age 0-14 years193. ALL is characterized by the rapid proliferation of lymphoid progenitor cells. B-cell acute lymphoblastic leukemia (B-ALL) originates from abnormal progenitor B cells, while T-ALL originates from abnormal progenitor T cells. These malignant progenitor cells, immature lymphoblasts, do not mature properly and
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