A Non-Cell-Autonomous Mode of DNA Damage Response in Soma of Caenorhabditis elegans

Abstract

Life has evolved a mechanism called DNA damage response (DDR) to sense, signal and remove/repair DNA damage, and its deficiency and dysfunction usually lead to genomic instability and development of cancer. The signaling mode of the DDR has been believed to be of cell-autonomy. However, the paradigm is being shifted with in-depth research into model organism Caenorhabditis elegans. Here, we mainly investigate the effect of DDR activation on the radiosensitivity of vulva of C. elegans, and first found that the vulval radiosensitivity is mainly regulated by somatic DDR, rather than the DDR of germline. Subsequently, the worm lines with pharynx-specific rescue of DDR were constructed, and it is shown that the 9-1-1-ATR and MRN-ATM cascades in pharynx restore approximately 90% and 70% of vulval radiosensitivity, respectively, through distantly regulating the NHEJ repair of vulval cells. The results suggest that the signaling cascade of DDR might also operate in a non-cell autonomous mode. To further explore the underlying regulatory mechanisms, the cpr-4 mutated gene is introduced into the DDR-rescued worms, and CPR-4, a cysteine protease cathepsin B, is confirmed to mediate the inter-tissue and inter-individual regulation of DDR as a signaling molecule downstream of 9-1-1-ATR. Our findings throw some light on the regulation of DNA repair in soma of C. elegans, and might also provide new cues for cancer prevention and treatment.

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

“…B cells, crucial components of the adaptive immune response, exhibited the highest UPR across all tumors, possibly due to their inherent high antibody demand in response to the cancer cells (Downs-Canner et al , 2022). Unexpectedly, we found that immune cells, traditionally associated with immune surveillance and response, showed high levels of DDR, indicating a potential cell-non-autonomous role for the DDR (Dai et al , 2022). The OSR was found to be high in CAFs across all tumor types, emphasizing a potential role for the OSR in the fibroblasts.…”