Journal of Molecular Biology
Volume 429, Issue 22, 10 November 2017, Pages 3409-3429
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Review
Molecular Basis for K63-Linked Ubiquitination Processes in Double-Strand DNA Break Repair: A Focus on Kinetics and Dynamics

https://doi.org/10.1016/j.jmb.2017.05.029Get rights and content

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.

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.

Introduction

DNA double-strand breaks (DSBs) are an insidious type of DNA damage that, left unaddressed, can lead to loss of genetic information, resulting in the onset of life threatening diseases including, for example, cancer, neurodegeneration, and metabolic disorders [1]. In response to such damaging DNA breaks, cells have evolved a sophisticated molecular defense system that leads to cell cycle checkpoint activation, cell cycle arrest, and ultimately repair of damaged DNA; the collective process is known as the DNA damage response [2]. Depending on cell cycle stage, DSBs are repaired either by non-homologous end-joining (NHEJ) or homologous recombination (HR) [3]. The NHEJ pathway carries out the joining of broken strands after end processing and is predominant throughout the cell cycle, whereas HR is active only in S and G2 phases, with the lost information in the broken strand regained through a homology search in the sister chromatid, thereby maintaining the fidelity of the repair process, as opposed to NHEJ, which is error-prone [4].

The repair of the broken strand by HR is enabled by timed recruitment and removal of different repair proteins [5]. These processes are guided by the action of different post-translational modifications such as phosphorylation, acetylation, methylation, ubiquitination, and SUMOylation that orchestrate recruitment and removal of different DNA repair proteins at break sites, ultimately facilitating the repair of broken DNA strands [6]. This review will outline various aspects of our current understanding of the molecular basis for K63-linked ubiquitination in DSB repair by HR, with a specific focus on the role that kinetics and dynamics for the underlying protein components and protein interactions within this system play in the repair process.

Ubiquitin (Ub) is a 76-residue globular protein, conjugated to other proteins through an amide bond between its C-terminal glycine and an acceptor lysine on substrate. The Ub fold is composed of a five-stranded β-sheet, α-helix, and a 310 helix. Ub possesses seven surface lysines, which can be enzymatically linked to the C terminus of a sequential Ub; this represents a versatile platform for building chains composed of distinct links and topologies. Ub conjugation to protein substrates is carried out by the sequential action of three enzymes. Initially, the Ub C-terminal glycine is covalently attached to Cys within an E1 enyzme through a thioester bond, followed by interaction of the E1 ~ Ub complex with an E2 Ub-conjugating (UBC) enzyme and subsequent Ub transfer to the E2 active site Cys. E3 Ub ligases bind E2 ~ Ub complexes and substrate proteins, leading to the formation of an amide bond between the ε-amino group of a substrate lysine and the C terminus of Ub [7], [8], [9]. K48-linked Ub chains typically signal for proteasomal degradation of substrate, whereas K63-linked chains serve as a signaling platform for various pathways and play a major role in the DSB repair process. Ub chains composed of other linkages are involved in several biological processes. However, their functional roles have not been explored to the same extent as K48- and K63-linked chains [10], [11].

Ub-like proteins possess a fold similar to that for Ub and include small Ub-like modifier (SUMO) and neural precursor cell expressed developmentally downregulated protein. These modifiers are involved in a number of signaling events in various cellular processes [12]. There are four different isoforms of SUMO, SUMO-1 shares ~ 45% sequence identity with SUMO-2 and 3 and lacks a SUMOylation motif, rendering it incapable of chain formation, whereas SUMO-2 and 3 share more than 90% sequence identity and form SUMO chains. SUMO is conjugated to substrates through the action of SUMO-specific E1, E2, and E3 enzymes in a manner similar to that for Ub. Initially, SUMO is transferred to its E1, the SAE1:SAE2 heterodimer, in an ATP-dependent manner. This is followed by conjugation to the only SUMO-specific E2, Ubc9, through a thioester bond, with the action of SUMO-specific E3 ligases ultimately attaching SUMO to substrates. SUMO-specific proteases, SENPs, remove SUMO modifications from substrates, regulating the signaling response. SUMO is recognized by proteins containing SUMO binding motifs such as the SUMO-interacting motif (SIM), a common and functionally important motif within a number of DSB repair proteins. It is composed of a stretch of hydrophobic residues flanked by acidic residues on one or both the sides of this hydrophobic module [13], [14]. Upon binding with SUMO, the SIM forms an intermolecular β-sheet. The nature of acidic residues flanking the SIM hydrophobic module determines the orientation of the β-strand within the intermolecular complex. In addition, these regions potentially contain phosphorylation sites that impact the affinity of the SIM and the orientation of the SIM strand that contributes to the intermolecular β-sheet [14], [15], [16], [17], [18].

The biological processes underlying the role of ubiquitination in the DNA damage response have been extensively reviewed [4]; in this section, we provide a brief overview of the HR repair pathway. Broken DNA strands induce chromatin relaxation, which is sensed by ataxia telangiectasia mutated (ATM) kinase, leading to its activation and interaction with the Mre11–Rad50–NBS1 complex (MRN complex), which binds broken DNA strands [6]. ATM phosphorylates histone H2AX at serine 139, and the resulting phosphorylated histone (γ-H2AX) acts as a recruitment scaffold for downstream repair proteins. Mediator of DNA damage checkpoint (MDC1) binds γ-H2AX, and as an ATM substrate, it is phosphorylated at damage sites to provide a binding platform for RNF8, an E3 Ub ligase [5]. A number of different Ub ligases, discussed in further detail below, lead to the conjugation of monoUb and Ub chains of different topologies at damage sites. These chains recruit repair proteins such as BRCA1, BRCA2, RAD51, and endonucleases such as EXO1 and CtIP and play important roles in repair pathway choice, chromatin reorganization, and repair pathway regulation [4]. Mechanistically, repair of DSBs by HR involves extensive resection of DNA ends by nucleases such as EXO1, DNA2, CtIP, and Mre11 of the MRN complex, resulting in the formation of single stranded DNA, which is then covered by replication protein A (RPA) [4]. In order to perform a homology search within the sister chromatid, RPA is exchanged with RAD51 by the assistance of BRCA2, and the resulting RAD51-ssDNA strand undergoes a homology search, followed by DNA synthesis, ligation, and conclusion of repair, thereby regaining the integrity of the chromosome [4], [19].

RNF20 and RNF40. Histone H2B monoubiquitination at K120 by this heterodimeric E3 Ub ligase regulates chromatin compaction, a reorganization step that is required for transcription elongation [20], [21], [22], [23], [24]. Histone H2B modification also occurs in response to DNA DSBs, in an ATM-dependent manner with RNF20–RNF40, resulting in the accumulation of early repair proteins such as XRCC, RAD51, and BRCA1, for both NHEJ and HR repair pathways [20], [23].

RNF2-BMI1: This heteromeric E3 Ub ligase belongs to the polycomb group proteins, an important group of epigenetic regulators. RNF2-BMI1-depleted cells show an impaired DNA damage response and increased sensitivity to radiation [25]. RNF2-BMI1 is responsible for the monoubiquitination of the core histone H2A at K119/K120 to enable gene silencing and to initiate DNA repair by facilitating the recruitment of the downstream repair proteins RAP80, 53BP1, and BRCA1 to damage sites [26], [27].

RNF8 and RNF168: The E3 Ub ligase RNF8 is recruited to damage sites through the binding of phosphorylated MDC1 via its Forkhead associated (FHA) domain [28], [29], [30]. RNF8 in conjunction with the heterodimeric E2/UBC enzyme variant (UEV) complex Ubc13-Mms2 synthesizes K63 chains on linker histone H1 [31]. A second E3 ligase, RNF168, then binds these K63 chains through an N-terminal Ub-binding domain (UBD1), which leads to monoubiquitination of the core histone H2A at K13/K15, in conjunction with the E2 UbcH5 [32], [33], [34], [35], [36]. It is also possible that RNF168, with Ubc13, can synthesize K63 chains at damage sites. Subsequently, K63 chain recognition by RAP80 in complex with BRCA1 and BRCC36 is obligatory for HR-mediated DNA repair [37], [38], [39]. The monoubiquitination of histone H2A at K13/15 and dimethylation of K20 at histone H4 are recognized by the Ub-dependent recruitment motif and Tudor domain of 53BP1, respectively, and result in initiation of NHEJ [40], [41], [42]. In its constitutive state, histone H4 with dimethylated K20 is bound to the polycomb group protein L3MBTL1 and demethylases. These components are likely removed through attachment of K48 Ub chains by the E3/E2 pair RNF8/UbcH8, followed by removal of L3MBTL1 by the AAA-ATPase VCP/p97 segregase [43], [44], [45], [46], [47], [48], [49]. The ubiquitination activities of RNF8/RNF168 are thought to be involved in determining the balance between recruitment of the repair protein 53BP1 and the BRCA1-A complex to damage sites, which determines if repair will proceed by NHEJ or HR.

HERC2: HERC2 is a 500-kDa protein belonging to the homologous to E6-AP carboxyl terminus (HECT) family of E3 Ub ligases that is required for RNF8- and RNF168-dependent ubiquitination [50]. Upon DNA damage, it is phosphorylated by ATM and binds the FHA domain of RNF8 to facilitate the accumulation of 53BP1 and BRCA1 at damage sites by promoting stabilization, or formation, of the RNF8–Ubc13 complex. HERC2 is not directly involved in K63 chain formation through the Ub ligase activity of its HECT domain [51], [52].

CHFR: The checkpoint with forkhead and RING finger domains (CHFR) E3 Ub ligase is recruited to sites of damage near the onset of repair, prior to recruitment of RNF8/RNF168 [53]. It contains FHA, really interesting new gene (RING), cysteine-rich domains, and a polyADP-ribose (PAR) binding zinc finger motif [54]. It interacts with the E2s Ubc13 and UbcH5C to synthesize K63- and K48-linked chains, respectively [54]. CHFR binds PAR modifications at sites of DNA damage through its PAR binding zinc finger motif and functions to ubiquitinate PAR polymerase 1, which leads to its early removal from the DSB repair process via proteasomal degradation [53].

RNF138: The E3 Ub ligase, RNF138, is recruited to damage sites through DNA binding mediated by its zinc finger domains; this promotes end resection and HR repair by ubiquitinating and displacing Ku80 from ssDNA and by binding Mre11 of the MRN complex through its zinc finger domains to recruit CtIP/EXO1 nuclease to damage sites [55], [56].

BRCA1-BARD1: BRCA1 is a tumor suppressor protein, found to be mutated in numerous malignancies; this protein is composed of an N-terminal RING and C-terminal BRCT domains, which facilitate interactions with multiple proteins to function in the maintenance of genome integrity [57]. BRCA1 interacts with BARD1, forming a heteromeric E3 Ub ligase that modifies substrates with different Ub linkages, including BRCA2, CtIP, and histone H2A [57], [58], [59], [60], [61], [62], [63], [64]. While BRCA1 has been the subject of intense research efforts, the molecular basis for its involvement in HR-driven DSB repair remains mysterious.

BRCC36: BRCC36 is a Jab1/Mpn/Mov34 (JAMM)/MPN+ deubiquitinase (DUB) that functions within a complex that includes RAP80, ABRAXAS, BRCA1, and MERIT40. This complex is recruited to sites of DNA damage through RAP80-mediated binding of K63 chains synthesized by RNF8/RNF168 [65]. BRCC36 selectively deubiquitinates K63 chains attached to γ-H2AX, thereby counteracting RNF8/RNF168-mediated ubiquitination at damage sites; these competing activities may be important for establishing the extent of the K63-linked polyubiquitination at DSBs [66].

Otubain 1 (OTUB1): OTUB1, a DUB belonging to the OTU class, acts as a negative regulator of RNF8 and RNF168-mediated K63 chain synthesis, with the inhibition separate from its catalytic activity as a K48-specific DUB [67]. Inhibition of K63 chain synthesis results through interaction with Ubc13, the cognate E2 for RNF8, which blocks the catalytic activity induced in Ubc13 by RNF8 [68], [69].

Ub-specific protease (USP) 3: The Ub modifications on K119/120 of histone H2A and on K13/15 of histone H2B generated by BMI1/RNF2 and RNF20-RNF40 are attenuated by USP3, an H2A- and H2B-specific DUB. Thus, USP3 is involved in maintenance of genomic integrity, potentially as a negative regulator of H2A/H2B-dependent recruitment of DNA repair proteins [70], [71].

USP11: USP11 is DUB that has been implicated in HR-driven DSB repair through the finding that it associates with, and deubiquitinates BRCA2, and affects the recruitment of RAD51 and 53BP1 to damage foci, although the molecular mechanisms are currently unclear [72], [73].

POH1: POH1/Rpn11 is a JAMM metalloprotease DUB that is associated with the 19S proteasome. POH1 activity associated with the proteasome results in cleavage of K63 chains at damage sites and limits the accumulation of 53BP1 at DSBs. In addition, it has also been shown to promote HR by facilitating the loading of RAD51 onto RPA-coated DNA strands for subsequent homology search and repair [74], [75].

BAP1: The DUB BAP1 associates with BRCA1 and is mutated in a number of cancers, particularly mesothelioma and melanoma. BAP1 is phosphorylated by ATM kinase and promotes repair of DSBs through PAR-polymerase-dependent recruitment of the polycomb DUB complex to DNA damage sites [76].

Ub carboxyl-terminal hydrolase (UCH) L5: This DUB is a component of both the INO80 chromatin remodeling complex and the 19S proteasome and has been implicated in the positive regulation of resection of DNA ends at DSBs and HR repair [77]. UCHL5 exerts this positive regulation by protecting the NFRKB protein from proteasomal degradation. NFRKB is a component of the INO80 complex, which is involved in the remodeling of chromatin through DNA end resection, and appears to upregulate resection through recruitment of EXO1.

Different isoforms of SUMO have been shown to gather at sites of DSBs along with the SUMO E3 ligases PIAS1 and PIAS4, whose activity is required for the proper formation of Ub chains at DSBs [78]. The polycomb group protein BMI1 has been shown to monoubiquitinate H2A, and its SUMOylation by CBX4 is a contributing factor for its accumulation at the DSB sites [79]. MDC1 is also SUMOylated upon DNA damage, a necessary step for its removal from sites of damage by the SUMO-targeted E3 Ub ligase RNF4 [80]. RAP80 binds K63 chains at damage sites through tandem Ub-interacting motifs (UIMs) and possesses a SIM adjacent to the UIMs that is important for its recruitment to the damage sites [81], [82]. RAP80 also interacts with the SUMO E2 Ubc9, and the ensuing SUMOylation is important for its functional role at DSBs [83]. BRCA1 is also modified by SUMO and co-localizes with SUMO1, SUMO2/3, and Ubc9 at DSB sites. SUMO modification of BRCA1 has been shown to enhance its Ub ligase activity in cells, which in turn is important for DSB repair [84]. The Mre11 protein is a constituent of the Mre11-Rad50-Xrs2 (MRX) complex in yeast (equivalent to the MRN complex in humans) and possesses two conserved SIMs. SIM1 is essential for the assembly of Mre11-Rad50-Xrs2 (MRX) complexes at DSB sites, and SIM2 is thought to recruit SUMOylated conjugates to Mre11, facilitating the subsequent recruitment of SUMO E2 Ubc9 and the SUMO E3 Ub ligase Siz2 to enhance the general SUMOylation of DNA repair proteins, presumably to assist repair [85].

Exonuclease EXO1 resects DNA ends during HR-mediated DSB repair and is constitutively SUMOylated by PIAS1/4-Ubc9, and this is a requirement for its Ub-dependent EXO1 degradation at stalled replication forks to avoid excessive resection of free DNA ends. Moreover, it was found that the deSUMOylating enzyme SENP6 interacts with EXO1 to antagonize this process [86].

The SUMO-specific protease SENP7 assists DSB repair by cleaving SUMO chains on KAP1, a key transcriptional regulator; this releases CHD3, a chromatin remodeling complex, which then brings about chromatin decondensation, a physical requirement for repair proteins to gain access to the damage sites [87].

DSBs induce the formation of protein conglomerates, known as ionizing radiation-induced foci, that are considered to be affinity platforms for the recruitment of DDR proteins to damage sites [4], [5], [88], [89]. A crucial early step in the development of ionizing radiation-induced foci, is the synthesis of K63-Ub chains on histone proteins, by the E3 ligases RNF8 and RNF168, in combination with the E2 heterodimer Mms2-Ubc13, which serve as recognition platforms for downstream repair proteins, as discussed previously. How the Ub landscape at DSBs is maintained by the flux of the ubiquitination cascade is not clearly understood. In this review, we focus largely on the structural, kinetic, and dynamic principles for the molecular mechanisms underlying the flux of K63-Ub signal, which is determined principally by the chain-building capacity of coupled E1, E2, and E3 enzyme activity and balanced by the counter-activity of DUBs, the p97 segregase, and the proteasome, including their respective chain recognition processes, and those of repair protein co-factors/receptors such as RAP80.

Section snippets

E1 Activating Enzymes

The first step in the Ub cascade involves the ATP-dependent activation of Ub by the E1 enzyme UBA1 [90]. As all subsequent steps in the ubiquitination cascade are dependent on the function of UBA1, it is not surprising that inhibition of UBA1 activity has severe consequences in cells. The E1 enzyme has a vital role in the regulation of the cell cycle, as deletions of the gene in yeast [91] and temperature-sensitive mutations in CHO cells [92], [93] show cell cycle arrest. Mutations in UBA1 or

E2 Enzymes and E3 Ub Ligases: Ubc13, Mms2, RNF8, and RNF168, the K63 Chain Builders

E2 enzymes bridge the barrier between activation of Ub by E1 enzyme and target selection by an E3 Ub ligase; given this central role, E2s have been extensively studied [107], [108]. There are approximately 40 human E2 enzymes that share a structural domain known as a UBC domain of approximately 150 residues, with the family divided into 4 classes depending on the presence of N- or C-terminal functional extensions [108], [109], [110]. The gap between Ub activation and final attachment to a

Deubiquitinating Enzymes, Terminating the Proteasome-Independent K63 Chain Signal

Deubiquitinases are critical components for a number of DNA damage response pathways [161]. The five families of DUBs include four cysteine isopeptidases: USPs, the UCHs, OTUs, Machado–Joseph disease, and the JAMM metallopeptidases [162], [163], [164].

RAP80 binds K63 chains using multivalency

Recruitment of the BRCA1-A complex to DNA damage sites is mediated through K63 chain recognition by the tandem UIM domains from RAP80, a process that is fundamental for DNA repair [4]. Individual UIMs consist of a short ~ 10-residue α-helix and bind Ub weakly, with affinities between 10 and 500 μM [156]. The UIMs from RAP80 bind mono-Ub with KD of ~ 700 μM [178], [179]. The KD for K63-Ub2 chain binding by the tandem UIMs from RAP80 (~ 20 μM) is sevenfold greater than that for K48-Ub2 chains (~ 160 μM),

Proteasome

The proteasome was initially characterized as a non-lysosomal, ATP-dependent enzyme that degraded abnormal and short-lived proteins [187], [188]. It was found to be composed of multiple subunits [189] and two major forms, an ATP- and Ub-independent 20S form and a Ub-dependent 26S form that contains the 20S particle [190], [191], [192], [193]. It was eventually recognized as the primary enzyme for general turnover of proteins and protein degradation for antigen presentation [194]. The 26S

Concluding Remarks and Future Directions

The flux of the ubiquitination cascade is fundamental for reshaping the chromatin landscape and facilitating the DSB repair process. K63-linked Ub chains are central to HR-mediated DSB repair, and although other chain topologies are also involved (K6 and K27, for example), a mechanistic and biochemical understanding for the role of different chains is not well developed. Arguably, the most well-understood step in the ubiquitination cascade is activation of the C terminus of Ub by E1 enzyme.

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to L.S. (MOP 110964), M.J.H. (MOP 119515), and J.N.M.G. (114975); by the Natural Sciences and Engineering Research Council (NSERC) Discovery grants to L.S. (2016-05778) and J.N.M.G. (2016-05163); and by the National Cancer Institute (NCI) program project grant PO1CA092584 to J.N.M.G.

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