Download Human monocytes are hypersensitive to genotoxins due to a DNA

DNA repair and misrepair in cells of the immune system
Bernd Kaina, Daniel Heylmann, Nancy Berte, Viviane Ponath and Markus Eich
Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131 Mainz,
Germany
T cells, monocytes, macrophages (Mphs) and dendritic cells (DCs) are key players in the
immune system. We studied the sensitivity of human monocytes and monocyte derived
Mphs and DCs to various genotoxic agents and found monocytes to be significantly more
sensitive than Mphs and DCs regarding overall cell kill and apoptosis following exposure to
methylating anticancer drugs, oxidating chemicals and ionising radiation (IR). The
hypersensitivity of monocytes was related to an increased level of DNA single- and doublestrand breaks, indicating a defect in base excision repair (BER) and DNA double-strand
break repair. Also, the DNA damage response was activated at lower dose levels compared
to Mphs and DCs. Expression studies on RNA and protein level revealed that monocytes
lack the repair proteins XRCC1, ligase III, PARP-1 and DNA-PKCS, whereas Mphs and DCs
and other blood cell populations including T cells express these repair factors. We conclude
that during maturation of monocytes into Mphs and DCs provoked by the cytokines GM-CSF
and IL-4, these repair genes become upregulated, resulting in protection against chemical
ROS and IR. Overall, the data revealed that human monocytes exhibit a BER defect that
makes them vulnerable to ionising radiation, chemical ROS and methylating genotoxicants,
including anticancer drugs. Currently, we translate the findings obtained with human blood
cells to mouse in which the response (radiation sensitivity) of different hematopoetic cells,
including monocytes, to ionising radiation is being studied. The biological significance of the
DNA repair defect in monocytes will briefly be discussed. References: Briegert and Kaina,
Cancer Res. 67, 26, 2007; Bauer et al., PNAS, 108, 21105, 2011; Bauer et al., PLoS One, 7,
339956, 2012; Heylmann et al., BBA Rev Cancer, 1846, 121, 2014; Supported By DFG,
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