期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 7, 页码 4080-4092出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt134
关键词
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资金
- Canadian Institutes of Health Research [MOP-102691]
- Terry Fox Foundation Strategic Training Initiative for Excellence in Radiation Research at Canadian Institute of Health Research
- Lawrence, Ila and William Gifford Scholarship Fund
- Radiation Medicine Program, University Health Network
APLF is a forkhead associated-containing protein with poly(ADP-ribose)-binding zinc finger (PBZ) domains, which undergoes ionizing radiation (IR)-induced and Ataxia-Telangiectasia Mutated (ATM)-dependent phosphorylation at serine-116 (Ser(116)). Here, we demonstrate that the phosphorylation of APLF at Ser(116) in human U2OS cells by ATM is dependent on poly(ADP-ribose) polymerase 3 (PARP3) levels and the APLF PBZ domains. The interaction of APLF at sites of DNA damage was diminished by the single substitution of APLF Ser(116) to alanine, and the cellular depletion or chemical inhibition of ATM or PARP3 also altered the level of accumulation of APLF at sites of laser-induced DNA damage and impaired the accumulation of Ser(116)-phosphorylated APLF at IR-induced gamma H2AX foci in human cells. The data further suggest that ATM and PARP3 participate in a common signalling pathway to facilitate APLF-Ser(116) phosphorylation, which, in turn, appears to be required for efficient DNA double-strand break repair kinetics and cell survival following IR. Collectively, these findings provide a more detailed understanding of the molecular pathway that leads to the phosphorylation of APLF following DNA damage and suggest that Ser(116)-APLF phosphorylation facilitates APLF-dependent double-strand break repair.
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