Regulation of oncogene-induced senescence by the MRE11 and TREX1 nucleases

Abstract

Oncogene-induced senescence (OIS) is a tumor-suppressive mechanism that arrests cell proliferation in response to oncogene-induced replication stress (RS). OIS also depends on the cGAS-STING pathway, which detects cytosolic DNA and promotes the expression of type I interferons (IFN) and pro-inflammatory cytokines. Whether and how the RS and IFN responses cooperate to promote OIS is currently unknown. Here, we show that the MRE11 nuclease promotes OIS in immortalized human fibroblasts overexpressing the H-RASV12 oncogene both by slowing replication forks and by activating the cGAS-STING pathway in response to RS. Interestingly, overexpression of TREX1, the major nuclease degrading cytosolic DNA, prevented RAS-induced senescence. In contrast, overexpression of a dominant negative mutant of TREX1 was sufficient to induce senescence in human fibroblasts, even in the absence of H-RASV12 induction. Collectively, these data suggest that the RS and IFN responses in OIS are functionally linked through a process involving the nucleases MRE11 and TREX1.

T‐Rex escaped from the cytosolic park: Re‐thinking the impact of TREX1 exonuclease deficiencies on genomic stability

“…Consistent with these findings, challenging normal human cells with interferon-β for several days resulted in the accumulation of micronuclei, DNA damage, and impaired cell proliferation (preprint [32] ). It is important to note that inflammatory signaling, and more specifically some cytokines and chemokines, have been shown to possess protumorigenic properties, such as the interleukins IL-6 and IL-8.…”

“…First, although ssDNA was detected in TREX1-deficient cells, this result does not preclude that dsDNA also accumulates, but remained undetected because of technical limitations. Second, recent evidence shows that TREX1 inactivation can lead to micronuclei accumulation [29][30][31] (and preprint [32] ) (see Figure 1). This result suggests that TREX1 deficiency leads to genomic instability by an unknown mechanism.…”

“…In recent studies, the absence of TREX1 has been associated with the occurrence of DNA damage and micronuclei, [30][31][32] particularly in astrocytes differentiated from induced pluripotent stem cells (iPSCs). [29] In these TREX1 KO astrocytes, the authors also observed an increased level of RNA:DNA hybrids (S9.6 blots).…”

“…[46] Whether RNA:DNA hybrids contribute to the inflammatory response in TREX1-deficient cells or auto-inflammatory disorders remains to be determined. It has been suggested that in the absence of TREX1, the type I interferon response and the subsequent production and secretion of cytokines and chemokines induce cytotoxic effects that destabilize genomic DNA [29] (and preprint [32] ).…”

“…It has been proposed that senescence occurs upon detection of DNA contained in micronuclei by the cGAS-STING pathway. [23][24][25] Intriguingly TREX1 deficiency leads to cellular senescence in several species [31,38] (and preprint [32] ). As described above, interferon-β supplementation in cultures of human fibroblasts was sufficient to arrest cell proliferation, to induce a senescence phenotype, and generate replication stress (preprint [32] ), suggesting that inflammation, for instance upon TREX1 inactivation, can alter chromosomal stability and cell fate; that is, a cell can follow multiple trajectories in between normal cycles of division, hyperproliferation, transformation, cell-cycle arrest, senescence, or cell-death.…”