The nuclear MRN complex links DNA damage to EGFR signaling

The DNA-damage response (DDR) is a comprehensive and complex network of phosphorylation-mediated signaling pathways that originates endogenously from the DNA lesion and activates intrinsic DNA repair mechanisms. The MRN is a complex of proteins, which consists of Mre11, Rad50 and Nbs1, and has an essential role in the recognition of DNA lesion and further recruitment of effector repair proteins.

We have previously demonstrated that macrophages constitute an important cell-nonautonomous physiological component of the DDR, termed “macrophage-assisted DNA damage repair”. Macrophages enhance DDR signaling and facilitate DNA damage repair. These activities are mediated by macrophage-derived HB-EGF that triggers EGFR signaling.

In this work we demonstrate that in cells suffering from DNA damage the nuclear MRN complex serves as a link connecting intra- nuclear DNA damage with ligand-dependent EGFR-signaling. When the MRN complex was inhibited in cells suffering from DNA damage, no phosphorylation of the EGFR and downstream signaling was observed.

MRN reprograms membrane growth factor singling (e.g. EGFR) and effects DNA damage repair.

This observation may shed light on the role played by EGFR in cancer; where over expression of this receptor is associated with resistance to radio- and chemotherapy.