Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 25, Issue 7, Pages 591-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0083-z
Keywords
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Funding
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- NIH [R01 CA132878, R01 GM116829, P50 CA 136393, R01 CA208244, R01CA142698]
- DoD [W81XWH-15-0564/OC140632, W81XWH-16-1-0391]
- Leukemia and Lymphoma Society Scholar grant
- Claudia Adams Barr Program in Innovative Basic Cancer Research
- Ovarian Cancer Research Fund Alliance
- Mayo Clinic Cancer Center Fraternal Order of Eagles Funds
- Cancer Research UK Career Development Fellowship [C52690/A19270]
- Cancer Research UK [19270] Funding Source: researchfish
- NATIONAL CANCER INSTITUTE [R01CA132878, P50CA136393, R01CA142698, R01CA208244] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM116829] Funding Source: NIH RePORTER
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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.
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