UFL1 promotes histone H4 ufmylation and ATM activation

Bo Qin, Jia Yu, Somaira Nowsheen, Minghui Wang, Xinyi Tu, Tongzheng Liu, Honglin Li, Liewei Wang and Zhenkun Lou ()
Additional contact information
Bo Qin: Mayo Clinic
Jia Yu: Mayo Clinic
Somaira Nowsheen: Mayo Clinic
Minghui Wang: Icahn School of Medicine at Mount Sinai
Xinyi Tu: Mayo Clinic
Tongzheng Liu: Jinan University
Honglin Li: Cancer Center, Georgia Regents University
Liewei Wang: Mayo Clinic
Zhenkun Lou: Mayo Clinic

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract The ataxia-telangiectasia mutated (ATM) kinase, an upstream kinase of the DNA damage response (DDR), is rapidly activated following DNA damage, and phosphorylates its downstream targets to launch DDR signaling. However, the mechanism of ATM activation is still not completely understood. Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. Monoufmylated histone H4 is important for Suv39h1 and Tip60 recruitment. Furthermore, ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and promoting ATM activation in a positive feedback loop. These findings reveal that ufmylation of histone H4 by UFL1 is an important step for amplification of ATM activation and maintenance of genomic integrity.

Date: 2019
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DOI: 10.1038/s41467-019-09175-0

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