DDR-mediated crosstalk between DNA-damaged cells and their microenvironment

Abstract

The DNA damage response (DDR) is an evolutionarily conserved signaling cascade that senses and responds to double-strand DNA breaks by organizing downstream cellular events, ranging from appropriate DNA repair to cell cycle checkpoints. In higher organisms, the DDR prevents neoplastic transformation by directly protecting the information contained in the genome and by regulating cell fate decisions, like apoptosis and senescence, to ensure the removal of severely damaged cells. In addition to these well-studied cell-autonomous effects, emerging evidence now shows that the DDR signaling cascade can also function in a paracrine manner, thus influencing the biology of the surrounding cellular microenvironment. In this context, the DDR plays an emerging role in shaping the damaged tumor microenvironment through the regulation of tissue repair and local immune responses, thereby providing a promising avenue for novel therapeutic interventions. Additionally, while DDR-mediated extracellular signals can convey information to surrounding, undamaged cells, they can also feedback onto DNA-damaged cells to reinforce selected signaling pathways. Overall, these extracellular DDR signals can be subdivided into two time-specific waves: a rapid bystander effect occurring within a few hours of DNA damage; and a late, delayed, senescence-associated secretory phenotype generally requiring multiple days to establish. Here, we highlight and discuss examples of rapid and late DDR-mediated extracellular alarm signals.

Keywords: DNA damage response; bystander effect; inflammation; microenvironment; senescence; senescence secretome; tissue damage.

FIGURE 1

The DNA damage response (DDR) generates alarm signals that are transmitted from the DNA-damaged cell to the extracellular microenvironment. (A) Rapid extracellular DDR signals occur in response to DNA damage and are transmitted to neighboring cells via direct cell–cell contact and paracrine signals. (B) Late extracellular DDR signals occur in response to persistent DNA damage signaling and are collectively known as the senescence-associated secretory phenotype (SASP).

FIGURE 2

Examples of molecular interactions between the DDR and outgoing–incoming extracellular damage signals. (A) Outgoing signal from the damaged cell: in response to persistent DNA-SCARS, molecular components of the DDR cascade lead to selected transcription factor activation and increased transcription of SASP factors such as IL-6. (B) Incoming damage to the undamaged cell: the presence of extracellular TGF-β can reinforce DDR-mediated p53 activity and trigger the formation of DNA-SCARS, which subsequently mediate senescence phenotypes, including increased secretion of SASP factors that reinforce a positive senescence feedback loop.