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.
Highlights
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
When we studied cellular function of UFM1 specific ligase 1 (UFL1), we unexpectedly found that UFL1 interacted with the MRN complex in a DNA damageinducible manner (Fig. 1a and Supplementary Figure 1a)
We found that UFL1 accumulated at double-strand break (DSB) site after triamcinolone acetonide (TA) treatment for 30 min (Fig. 1c)
Summary
When we studied cellular function of UFL1, we unexpectedly found that UFL1 interacted with the MRN complex in a DNA damageinducible manner (Fig. 1a and Supplementary Figure 1a). Following ionizing irradiation (IR), nuclear UFL1 protein formed discrete nuclear foci and colocalized with γH2AX (Fig. 1b and Supplementary Figure 1b), indicating that UFL1 relocalizes to DNA lesions. In NBST cells, UFL1 failed to form nuclear foci following DNA damage, while reconstitution of WT NBS1 resulted in the accumulation of UFL1 to DSBs (Fig. 1f and Supplementary Figure 1f). Depletion of UFL1 did not affect the recruitment of NBS1 to DSBs (Supplementary Figure 1g) Taken together, these results suggest that the MRN complex is important for UFL1 recruitment to DSBs. Activation of ATM signaling by UFL1. DNA-PK phosphorylation in response to IR was not affected (Fig. 2a)
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