Chaperoning HMGA2 Protein Protects Stalled Replication Forks in Stem and Cancer Cells
Menée in vitro, cette étude met en évidence des mécanismes par lesquels l'expression de HGMA2, une protéine chaperon connue pour son implication dans le maintien de l'intégrité du génome des cellules souches embryonnaires, protège également les cellules souches cancéreuses de l'action des traitements endommageant l'ADN
Maintaining genome integrity requires the accurate and complete replication of chromosomal DNA. This is of the utmost importance for embryonic stem cells (ESCs), which differentiate into cells of all lineages, including germ cells. However, endogenous and exogenous factors frequently induce stalling of replication forks in every cell cycle, which can trigger mutations and chromosomal instabilities. We show here that the oncofetal, nonhistone chromatin factor HMGA2 equips cells with a highly effective first-line defense mechanism against endonucleolytic collapse of stalled forks. This fork-stabilizing function most likely employs scaffold formation at branched DNA via multiple DNA-binding domains. Moreover, HMGA2 works independently of other human factors in two heterologous cell systems to prevent DNA strand breaks. This fork chaperone function seemingly evolved to preserve ESC genome integrity. It is hijacked by tumor (stem) cells to also guard their genomes against DNA-damaging agents widely used to treat cancer patients. "HMGA2 colocalizes with key replication factors "HMGA2 physically stabilizes branched DNA structures in vitro "HMGA2 prevents DSBs at stalled forks in embryonic stem and cancer cells "HMGA2 enhances survival after replication stress in two heterologous cell systems Replication fork stalling inevitably occurs in all dividing cells, and prolonged stalling leads to DNA strand breaks that trigger chromosomal instabilities and apoptosis. Fork stalling is also induced during cancer therapy targeting DNA. In this study, Dröge and colleagues show that by forming scaffolds at branched DNA structures, endogenous HMGA2 proteins chaperone stalled forks in embryonic stem and cancer cells. This protective activity promotes genome stability and cell survival, and identifies HMGA2 as a specific target for cancer combination therapy.
http://linkinghub.elsevier.com/retrieve/pii/S221112471400031X 2014