Format

Send to

Choose Destination
Cell Rep. 2019 Jul 9;28(2):394-407.e6. doi: 10.1016/j.celrep.2019.06.043.

Loss of Slug Compromises DNA Damage Repair and Accelerates Stem Cell Aging in Mammary Epithelium.

Author information

1
Department of Developmental, Molecular, & Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, Boston, MA 02111, USA.
2
Department of Biomedical Sciences, Quinnipiac University, Hamden, CT 06518, USA.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
4
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
5
Department of Radiation Oncology, Tufts Medical Center, Boston, MA 02111, USA.
6
Department of Developmental, Molecular, & Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: charlotte.kuperwasser@tufts.edu.

Abstract

DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but also promote tissue aging. Because mice lacking Slug/Snai2 exhibit limited stem cell activity, including luminobasal differentiation, and are protected from mammary cancer, we reasoned that Slug might regulate DNA damage checkpoints in mammary epithelial cells. Here, we show that Slug facilitates efficient execution of RPA32-mediated DNA damage response (DDR) signaling. Slug deficiency leads to delayed phosphorylation of ataxia telangiectasia mutated and Rad3-related protein (ATR) and its effectors RPA32 and CHK1. This leads to impaired RAD51 recruitment to DNA damage sites and persistence of unresolved DNA damage. In vivo, Slug/Snai2 loss leads to increased DNA damage and premature aging of mammary epithelium. Collectively, our work demonstrates that the mammary stem cell regulator Slug controls DDR checkpoints by dually inhibiting differentiation and facilitating DDR repair, and its loss causes unresolved DNA damage and accelerated aging.

KEYWORDS:

DNA damage; DNA damage checkpoints; Slug; aging; mammary gland; stem cells

PMID:
31291576
DOI:
10.1016/j.celrep.2019.06.043
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center