UFL1 promotes histone H4 ufmylation and ATM activation

Bo Qin; Jia Yu; Somaira Nowsheen; Minghui Wang; Xinyi Tu; Tongzheng Liu; Honglin Li; Liewei Wang; Zhenkun Lou

doi:10.1038/s41467-019-09175-0

UFL1 promotes histone H4 ufmylation and ATM activation

Nat Commun. 2019 Mar 18;10(1):1242. doi: 10.1038/s41467-019-09175-0.

Authors

Bo Qin^{1

2}, Jia Yu², Somaira Nowsheen^{1

3}, Minghui Wang⁴, Xinyi Tu¹, Tongzheng Liu⁵, Honglin Li⁶, Liewei Wang², Zhenkun Lou⁷

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. lou.zhenkun@mayo.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Acid Anhydride Hydrolases
Ataxia Telangiectasia Mutated Proteins / metabolism*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
DNA Breaks, Double-Stranded
DNA Repair Enzymes / metabolism
DNA Repair*
DNA-Binding Proteins / metabolism
HEK293 Cells
Histones / metabolism*
Humans
Lysine Acetyltransferase 5 / metabolism
MRE11 Homologue Protein / metabolism
Methyltransferases / metabolism
Nuclear Proteins / metabolism
Phosphorylation / genetics
Protein Processing, Post-Translational / genetics*
RNA, Small Interfering / metabolism
Repressor Proteins / metabolism
Serine / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

Cell Cycle Proteins
DNA-Binding Proteins
Histones
MRE11 protein, human
NBN protein, human
Nuclear Proteins
RNA, Small Interfering
Repressor Proteins
Serine
SUV39H1 protein, human
Methyltransferases
KAT5 protein, human
Lysine Acetyltransferase 5
Ubiquitin-Protein Ligases
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
MRE11 Homologue Protein
Acid Anhydride Hydrolases
RAD50 protein, human
UFL1 protein, human
DNA Repair Enzymes

Abstract

Publication types

MeSH terms

Substances

Grants and funding