In eukaryotic cells,DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA.These DNA damage responses serve to maintain genome stability and prevent...In eukaryotic cells,DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA.These DNA damage responses serve to maintain genome stability and prevent accumulation of genetic mutations and development of cancer.The p38 MAPK was previously implicated in cellular responses to several types of DNA damage.However,the role of each of the four p38 isoforms and the mechanism for their involvement in DNA damage responses remained poorly understood.In this study,we demonstrate that p38γ,but not the other p38 isoforms,contributes to the survival of UV-treated cells.Deletion of p38γsensitizes cells to UV exposure,accompanied by prolonged S phase cell cycle arrest and increased rate of apoptosis.Further investigation reveal that p38γis essential for the optimal activation of the checkpoint signaling caused by UV,and for the efficient repair of UVinduced DNA damage.These findings have established a novel role of p38γin UV-induced DNA damage responses,and suggested that p38γcontributes to the ability of cells to cope with UV exposure by regulating the checkpoint signaling pathways and the repair of damaged DNA.展开更多
基金This work is supported by grants from National Institute of Health,USA(CA106768,CA131231 and RR025744 to P.S.,AI041637 and AI068896 to J.H.,and CA102361 and CA140972 to XW)an international collaborative grant from National Science Foundation in China(30828019 to P.S.and J.H.).The Scripps manuscript number is 20721.
文摘In eukaryotic cells,DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA.These DNA damage responses serve to maintain genome stability and prevent accumulation of genetic mutations and development of cancer.The p38 MAPK was previously implicated in cellular responses to several types of DNA damage.However,the role of each of the four p38 isoforms and the mechanism for their involvement in DNA damage responses remained poorly understood.In this study,we demonstrate that p38γ,but not the other p38 isoforms,contributes to the survival of UV-treated cells.Deletion of p38γsensitizes cells to UV exposure,accompanied by prolonged S phase cell cycle arrest and increased rate of apoptosis.Further investigation reveal that p38γis essential for the optimal activation of the checkpoint signaling caused by UV,and for the efficient repair of UVinduced DNA damage.These findings have established a novel role of p38γin UV-induced DNA damage responses,and suggested that p38γcontributes to the ability of cells to cope with UV exposure by regulating the checkpoint signaling pathways and the repair of damaged DNA.
