K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair.

 2018 Jun 5;11(533). pii: eaar8133. doi: 10.1126/scisignal.aar8133.
Liu P1,2, Gan W3, Su S2, Hauenstein AV4, Fu TM4, Brasher B5, Schwerdtfeger C5, Liang AC6, Xu M7,8, Wei W1.

Author information

1
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. pengda_liu@med.unc.edu wwei2@bidmc.harvard.edu.
2
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
5
Boston Biochem Inc., Cambridge, MA 02139, USA.
6
Department of Genetics and Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115, USA.
7
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Abstract

Polyubiquitylation is canonically viewed as a posttranslational modification that governs protein stability or protein-protein interactions, in which distinct polyubiquitin linkages ultimately determine the fate of modified protein(s). We explored whether polyubiquitin chains have any nonprotein-related function. Using in vitro pull-down assays with synthetic materials, we found that polyubiquitin chains with the Lys63 (K63) linkage bound to DNA through a motif we called the "DNA-interacting patch" (DIP), which is composed of the adjacent residues Thr9, Lys11, and Glu34 Upon DNA damage, the binding of K63-linked polyubiquitin chains to DNA enhanced the recruitment of repair factors through their interaction with an Ile44 patch in ubiquitin to facilitate DNA repair. Furthermore, experimental or cancer patient-derived mutations within the DIP impaired the DNA binding capacity of ubiquitin and subsequently attenuated K63-linked polyubiquitin chain accumulation at sites of DNA damage, thereby resulting in defective DNA repair and increased cellular sensitivity to DNA-damaging agents. Our results therefore highlight a critical physiological role for K63-linked polyubiquitin chains in binding to DNA to facilitate DNA damage repair.

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PMID:
 
29871913
 
DOI:
 
10.1126/scisignal.aar8133