Macrophages regulate the systemic response to DNA damage by a cell nonautonomous mechanism

Anat Geiger-Maor, Avital Guedj, Sharona Even-Ram, Yoav Smith, Eithan Galun, Jacob Rachmilewitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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. Here we describe a macrophage-dependent mechanism that regulates the response to DNA damage. We demonstrate that human monocytes, by releasing macrophage-derived HB-EGF, enhance DDR in neighboring cells suffering from DNA damage. Consequently, HB-EGF-treated cells exhibit higher double-strand break (DSB) rejoining and display lower levels of residual DSBs. Diethylnitrosamine (DEN) injection induce DSBs along with elevation in the number of macrophages and HB-EGF expression. Significantly, macrophage depletion or blocking HB-EGF activity results in higher levels of nonrepairable DSBs, suggesting that macrophages play a role in the resolution of DNA damage via HB-EGF. This study establishes that macrophages, acting through the activation of the EGFR cascade, constitute an important cell nonautonomous physiologic component of the DDR and points to a unique role played by immune cells in maintaining genome integrity.

Original languageEnglish
Pages (from-to)2663-2673
Number of pages11
JournalCancer Research
Volume75
Issue number13
DOIs
StatePublished - 1 Jul 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 American Association for Cancer Research.

Fingerprint

Dive into the research topics of 'Macrophages regulate the systemic response to DNA damage by a cell nonautonomous mechanism'. Together they form a unique fingerprint.

Cite this