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Cancer Res. 2015 Jul 1;75(13):2663-73. doi: 10.1158/0008-5472.CAN-14-3635. Epub 2015 May 14.

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism.

Author information

1
Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
2
Hadassah Human Embryonic Stem Cell Research Center, Goldyne Savad Institute of Gene Therapy, Hadassah- Hebrew University Medical Center, Jerusalem, Israel.
3
Genomic Data Analysis Unit of the Hebrew University Medical School, Jerusalem, Israel.
4
Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. rjacob444@gmail.com.

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.

PMID:
25977329
DOI:
10.1158/0008-5472.CAN-14-3635
[Indexed for MEDLINE]
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