Molecular Basis for K63-Linked Ubiquitination Processes in Double-Strand DNA Break Repair: A Focus on Kinetics and Dynamics. Issue 22 (10th November 2017)

• Record Type: Journal Article
• Authors: Lee, Brian L.; Singh, Anamika; Mark Glover, J.N.; Hendzel, Michael J.; Spyracopoulos, Leo
• Is Part Of: Journal of molecular biology. Volume 429:Issue 22(2017)
• Page Start: 3409
• Page End: 3429
• Publication Date: 2017-11-10
• Subjects: DSB double-strand break -- NHEJ non-homologous end-joining -- HR homologous recombination -- Ub ubiquitin -- UBC Ub-conjugating -- SUMO small Ub-like modifier -- SIM SUMO-interacting motif -- ATM ataxia telangiectasia mutated -- MRN Mre11–Rad50–NBS1 complex -- MDC1 mediator of DNA damage checkpoint -- RPA replication protein A -- FHA forkhead associated -- UEV UBC enzyme variant -- UBD Ub-binding domain -- HECT homologous to E6-AP carboxyl terminus -- CHFR checkpoint with forkhead and RING finger domains -- RING really interesting new gene -- PAR polyADP-ribose -- JAMM Jab1/Mpn/Mov34 -- DUB deubiquitinase -- OTU ovarian tumor protease -- USP Ub-specific proteases -- UCH Ub carboxyl-terminal hydrolase -- UIM Ub-interacting motif -- MRX Mre11-Rad50-Xrs2 -- SPR surface plasmon resonance -- SAXS small angle X-ray scattering -- PML promyelocytic leukaemia -- LRM ligand recognition motif -- MIU motif interacting with ubiquitin -- AMSH associated molecule with the SH3 domain of STAM -- SEC-MALS size exclusion chromatography with multi-angle light scattering -- CRL cullin-RING ligase; ubiquitination -- DNA damage response -- enzyme kinetics -- protein dynamics -- protein–protein-interactions; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2017.05.029
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: Cells are exposed to thousands of DNA damage events on a daily basis. This damage must be repaired to preserve genetic information and prevent development of disease. The most deleterious damage is a double-strand break (DSB), which is detected and repaired by mechanisms known as non-homologous end-joining (NHEJ) and homologous recombination (HR), which are components of the DNA damage response system. NHEJ is an error-prone first line of defense, whereas HR invokes error-free repair and is the focus of this review. The functions of the protein components of HR-driven DNA repair are regulated by the coordinated action of post-translational modifications including lysine acetylation, phosphorylation, ubiquitination, and SUMOylation. The latter two mechanisms are fundamental for recognition of DSBs and reorganizing chromatin to facilitate repair. We focus on the structures and molecular mechanisms for the protein components underlying synthesis, recognition, and cleavage of K63-linked ubiquitin chains, which are abundant at damage sites and obligatory for DSB repair. The forward flux of the K63-linked ubiquitination cascade is driven by the combined activity of E1 enzyme, the heterodimeric E2 Mms2-Ubc13, and its cognate E3 ligases RNF8 and RNF168, which is balanced through the binding and cleavage of chains by the deubiquitinase BRCC36, and the proteasome, and through the binding of chains by recognition modules on repair proteins such as RAP80. We highlight a number of aspects regarding our current understanding for the role of kinetics and dynamics in determining the function of the enzymes and chain recognition modules that drive K63 ubiquitination. Graphical Abstract: Highlights: NHEJ or HR repairs DNA DSBs. HR repair is error-free and regulated by ubiquitination and SUMOylation. K63 ubiquitin chains are abundant at repair sites and obligatory for repair. The flux of the chain-building cascade reshapes the chromatin landscape and facilitates repair. The role of kinetics and dynamics in driving the flux of the chain-building machinery is emerging.