Beyond DNA damage response: Immunomodulatory attributes of CHEK2 in solid tumors (IMAGE)
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Figure 1: The proposed effect of CHEK2 loss of function on cytotoxic T-cell recruitment at different organizational levels. (A) Double stranded breaks (DSB) are resolved through either homologous recombination or the non-homologous end joining pathway. In the loss of CHEK2 function scenario, the functionality of the HR pathway is reduced, and the ability to resolve double stranded breaks fully and accurately, is diminished. Subsequently, the DNA damage response pathway attempts to resolve the DSB through the NHEJ pathway, which is less accurate and leads to the accumulation of somatic mutations. (B) The accumulation of somatic mutations produces fragments of DNA that exit the nucleus through vesicles. When DNA is released from these vesicles, cGAS recognizes the presence of cytosolic DNA and activates the downstream effectors of the cGAS-STING pathway. (C) The secondary mechanism of immune cell recruitment including CD8 T cell infiltration because of CHEK2 deficiency maybe through the downstream signaling cascade leading to the production of Type I Interferon and chemotaxis inducing cytokines following cGAS-STING pathway activation.
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