2. Academic Validation
  3. UFL1 promotes histone H4 ufmylation and ATM activation

UFL1 promotes histone H4 ufmylation and ATM activation

  • Nat Commun. 2019 Mar 18;10(1):1242. doi: 10.1038/s41467-019-09175-0.
Bo Qin 1 2,  Jia Yu 2,  Somaira Nowsheen 1 3,  Minghui Wang 4,  Xinyi Tu 1,  Tongzheng Liu 5,  Honglin Li 6,  Liewei Wang 2,  Zhenkun Lou 7
Affiliations

Affiliations

  • 1 Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 2 Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.
  • 3 Mayo Medical Scientist Training Program, Mayo Medical School and Mayo Graduate School, Mayo Clinic, Rochester, MN, 55905, USA.
  • 4 Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
  • 5 Institute of Tumor Pharmacology, Jinan University, 510632, Guangzhou, China.
  • 6 Department of Biochemistry & Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
  • 7 Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. [email protected].
PMID: 30886146 DOI: 10.1038/s41467-019-09175-0
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.

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