| Structural highlights
Function
[TIRR_HUMAN] Key regulator of TP53BP1 required to stabilize TP53BP1 and regulate its recruitment to chromatin (PubMed:28241136). In absence of DNA damage, interacts with the tandem Tudor-like domain of TP53BP1, masking the region that binds histone H4 dimethylated at 'Lys-20' (H4K20me2), thereby preventing TP53BP1 recruitment to chromatin and maintaining TP53BP1 localization to the nucleus (PubMed:28241136). Following DNA damage, ATM-induced phosphorylation of TP53BP1 and subsequent recruitment of RIF1 leads to dissociate NUDT16L1/TIRR from TP53BP1, unmasking the tandem Tudor-like domain and allowing recruitment of TP53BP1 to DNA double strand breaks (DSBs) (PubMed:28241136). Binds U8 snoRNA (PubMed:18820299).[1] [2]
Publication Abstract from PubMed
Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications. The DNA repair factor 53BP1 is a rare example of a protein whose post-translational modification-binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation within chromatin, an activity directly inhibited by the 53BP1-binding protein TIRR. X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a unique regulatory mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation that abolishes TIRR-mediated regulation in cells renders 53BP1 hyperactive in response to DSBs, highlighting the key inhibitory function of TIRR. This 53BP1 inhibition is relieved by TIRR-interacting RNA molecules, providing proof-of-principle of RNA-triggered 53BP1 recruitment to DSBs.
Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein.,Botuyan MV, Cui G, Drane P, Oliveira C, Detappe A, Brault ME, Parnandi N, Chaubey S, Thompson JR, Bragantini B, Zhao D, Chapman JR, Chowdhury D, Mer G Nat Struct Mol Biol. 2018 Jul 2. pii: 10.1038/s41594-018-0083-z. doi:, 10.1038/s41594-018-0083-z. PMID:29967538[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Taylor MJ, Peculis BA. Evolutionary conservation supports ancient origin for Nudt16, a nuclear-localized, RNA-binding, RNA-decapping enzyme. Nucleic Acids Res. 2008 Oct;36(18):6021-34. doi: 10.1093/nar/gkn605. Epub 2008, Sep 27. PMID:18820299 doi:http://dx.doi.org/10.1093/nar/gkn605
- ↑ Drane P, Brault ME, Cui G, Meghani K, Chaubey S, Detappe A, Parnandi N, He Y, Zheng XF, Botuyan MV, Kalousi A, Yewdell WT, Munch C, Harper JW, Chaudhuri J, Soutoglou E, Mer G, Chowdhury D. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature. 2017 Mar 9;543(7644):211-216. doi: 10.1038/nature21358. Epub 2017 Feb 27. PMID:28241136 doi:http://dx.doi.org/10.1038/nature21358
- ↑ Botuyan MV, Cui G, Drane P, Oliveira C, Detappe A, Brault ME, Parnandi N, Chaubey S, Thompson JR, Bragantini B, Zhao D, Chapman JR, Chowdhury D, Mer G. Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. Nat Struct Mol Biol. 2018 Jul 2. pii: 10.1038/s41594-018-0083-z. doi:, 10.1038/s41594-018-0083-z. PMID:29967538 doi:http://dx.doi.org/10.1038/s41594-018-0083-z
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