Abstract
DNA double-strand breaks (DSBs) are cytotoxic DNA lesions that must be repaired as soon as possible because it can cause chromosomal aberrations and cell death. Homologous recombination (HR) and nonhomologous end joining (NHEJ) are the pathways that mainly repair these ruptures. HR process is finely regulated by synchronized posttranslational modifications including phosphorylation, ubiquitylation, and SUMOylation. The ubiquitin (Ub) modifications at damaged chromatin serve as recruitment platforms for DSB repair complexes by facilitating binding sites or regulating the interaction between proteins. Thus, SUMOylation has been associated with protein interaction, enzymatic activity, and chromatin mobility. Several DNA damage factors have been found to be ubiquitylated and SUMOylated including histones (H2AX) and proteins such as Mre11, Rad51, NBS1, and BRCA1. Regarding ubiquitylation-mediated regulation of DNA repair, RNF168 and RNF8 E3 ligases have turned out to be a key step in DNA damage repair regulation. Interestingly, there is evidence that the Ub signaling mechanism is ancestral, and this emphasizes its importance.
Keywords
- ubiquitylation
- DSB
- SUMOylation
- DNA repair
- chromatin architecture
1. Introduction
Genome integrity is compromised by the constant attack from exogenous and endogenous DNA-damaging factors such as radiation, carcinogens, reactive radicals, and errors in DNA replication. The most deleterious DNA lesion is the double-strand breaks (DSBs) because failure to repair them results in diverse changes in DNA such as mutations or chromosomal rearrangements. Thus, to maintain genomic stability, cells have developed an elaborate DNA damage response (DDR) system to detect, signal, and repair the DNA lesions [1, 2, 3].
DSBs are repaired by two main pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR). NHEJ works with a fast kinetics throughout the cell cycle and joins broken DNA ends without the need of extended complementary sequences leading to an error-prone repair [4]. HR, on the other hand, takes longer and is restricted to the S and G2 phases of the cell cycle since an intact sister chromatid is required for repair based on a homologous template, and thus this process is carried out error-free [5].
HR is an evolutionary well-conserved mechanism, where nucleolytic degradation of the 5′ end in the DSB produces long 3′-single-stranded DNA (ssDNA) overhangs, and this is referred as DNA end resection [6, 7]. These dangling 3′ ends must be protected from nucleases, and the formation of tertiary structures is accomplished by
2. Ubiquitin in DSB response
Ubiquitin (Ub) is a 76 amino acid protein with seven lysine residues that can form polyubiquitin chains of eight different linkages (K6, K11, K27, K33, K48, K63, and Met1) as well as mixed and branched chains (Figure 1) [13]. The generation of different protein Ub chains provides structural diversity allowing proteins with specific Ub-binding domains (UBDs) to discriminate between these different structures. For example, Ub K48 and K63 polyubiquitin chains are structurally distinct and are differentially recognized by proteins containing different UBDs [14]. To date, over 200 proteins with at least 20 different types of UBDs have been identified that bind to different Ub structures in a noncovalent manner [15]. The ability of distinct protein Ub structures to specifically bind to proteins containing a particular UBD is important for generating specificity of protein-protein interactions and targeting proteins to different pathways and fates. For example, monoubiquitylation can regulate DNA repair, regulation of histone function, gene expression, and receptor endocytosis (Figure 1) [16].
Due to the ability of the Ub molecule to be conjugated onto diverse substrate lysine(s), protein ubiquitylation is a multifunction-oriented process using its own lysines or via its N-terminal methionine residues, to generate a diverse range of structures and therefore modify activities in protein targets [17]. Each linkage kind promotes a different protein conformation providing a certain degree of diversity, thus exposing a specific Ub-binding domain (UBD) with a particular function like favoring or inhibiting protein-protein interactions, protein localization, and/or degradation. To illustrate this, polyubiquitin chains attached to a protein in its Ub K63 linkage could mostly apply to proteins mainly distributed in the lysosome/endocytosis, DNA repair, and signal transduction (Figure 1). The ubiquitylation process is a bit complex; it is carried out mainly by three proteins: E1 (activating enzyme), E2 (conjugating enzyme), and E3 (ligating enzymes). E1 activates ubiquitin (Ub) C-terminus by generating a thioester-linked E1~Ub conjugate which is dependent on adenosin-5′ triphosphate (ATP). Then, via a trans-thiolation reaction, the E2 active cysteine site receives the activated Ub from E1. E3 and E2 cooperate to facilitate the transfer of Ub onto a substrate lysine (K) of a protein target to form an isopeptide bond resulting in a ubiquitylated protein. E3 enzymes have been grouped in three E3 families: RING families (
In order to promote the isopeptide formation between the lysine residue of the target protein and the glycine of the Ub C-terminus, the RING E3 ligase recruits both the E2-Ub conjugate and protein target. In contrast, HECT E3 ligases take Ub from E2-Ub conjugate on a catalytic cysteine and transfer the ubiquitin to a target lysine. On the other hand, the hybrid RING/HECT E3 ligase N-terminal RING1 domain works like the RING E3 ligases since they bind and recognize the E2-Ub conjugate, while the RING2 domain catalytic cysteine accepts a Ub molecule from E2-Ub conjugate before it is transferred to the target lysine [19]. Protein ubiquitylation is reversible through deubiquitylating enzymes (DUBs), which have the ability to cleave single Ub or polyubiquitin chains from targeted proteins.
Rad6, a postreplication repair (PRR) protein [20], was the first enzyme involved in an ubiquitylation role. Also, a mutation in ubiquitin K63R caused sensitivity to UV and DNA damage in yeast [21]. Rap80 bears a tandem ubiquitin-interacting motif (UIM) that binds to K63 linkages in vitro and is attached to Ub through K63 linkages in vivo upon DNA damage. In humans Rap80 binds to BRCA1 (
RING finger protein 8 (RNF8) is an E3 ligase that catalyzes Ub K63 linkages at DSBs in mammals. Once H2AX is phosphorylated by ATM in regions that flank DSBs, MDC1 (
3. SUMO in DSB response
In 1996,
Because SUMO2 and SUMO3 isoforms are not distinguished by antibodies, they are usually referred as SUMO2/SUMO3. Further, recent data for SUMO4 indicates that this is processed to its mature form only under particular conditions [31].
4. Ubiquitin and SUMOylation of DNA end resection machinery
In response to DNA double-strand break (DSB), various elements of DNA damage response are recruited to these injured sites. The gathering of these molecules at damage sites becomes visible as foci (or ionizing radiation induced foci (IRIF)) in the nucleus, which can be observed via immunofluorescence microscopy [38].
In the initial stage of HR, the DSB ends are resected in such a way that 3′-single-strand DNA (ssDNA) overhangs are generated. This process is started by the conserved MRX (comprises by Mre11-Rad50-Xrs2) nuclease complex, which in collaboration with Sae2 in yeast, and by the MRN (including Mre11-Rad50-NBS1) complex in conjunction with CtIP (
After the resection process, the ssDNA overhangs are speedily coated by RPA (
The E3 ligase RNF8 ubiquitylates NBS1 at Lys-435, mainly, and at Lys-6 that is promoted likely by E2 ligase UbcH5C. Ubiquitylation of NBS1 was detected before and after DNA damage. Studies with RNF8 mutants suggest that the interaction of RNF8 with NSB1 is mediated by the N-terminus of RNF8. RNF8 and certain RNF8 ubiquitylation activities are needed for efficient localization of NBS1 and MRN recruitment to DSB (Figure 3) [49].
During DNA end resection process, the participation of deubiquitinase (DUB) activity of USP4 (
After DNA damage, Sae2 is SUMOylated at a single conserved lysine residue (K97) mediated by Ubc9-Siz1/Siz2, and the levels of soluble Sae2 were increased [55]. An indication of Sae2 SUMOylation critical role for DNA end resection was observed in Sae2-K97R mutant cells, in which the processing and repair of DSBs were decreased [42].
It has been shown that human EXO1 is targeted for degradation by the ubiquitin-proteasome pathway. Recently, it was demonstrated that PIAS1/PIAS4-UBC9-mediated EXO1 SUMOylation (Figure 3) is a prerequisite for EXO1 ubiquitylation [56]. Even though the interactions between EXO1 and SENP6 de-SUMOylating enzyme [57], EXO1 with SCF-cyclin F E3 ubiquitin ligase (Figure 3) [12], and EXO1 with UCHL5 [58] have been studied, their participation in DNA end resection process has not been determined. PIAS1 and/or PIAS4 SUMOylates BRCA1 when it is localized at DSB sites, enhancing its ubiquitin ligase activity [36]. The MRN, Ubc9, and Siz2 allows
5. Chromatin remodeling
In general, any process like transcription, replication, and DNA repair requires a certain degree of chromatin access; therefore, remodeling is an important prerequisite for factors related to such processes. The participation of ubiquitylation and SUMOylation role on DNA repair on chromosome topology are very important in chromatin structure and organization.
3C (
Using 3C-based technology, it has been possible to determine intrachromosomal contacts within TADs (
These effects can be classified as bulky or large and localized.
5.1. Bulky effects
The bulky effects have been observed as long-range movement; for example, the case of localizing the VP16 activator to the nuclear periphery resulted in its relocalization to the nuclear interior, and also when RNA pol I transcription was inhibited, this caused movement of chromatin to the nucleolar periphery (Figure 4) [63].
Interestingly in
It has recently been shown that INO80 also promotes chromatin movement due to DSB in telomeres, and this depends on actin polymerization [66]. It has been proposed that these movements contribute at least in part to homology searches during HR [67]. In the same line, a recent finding showed that MEC1-driven phosphorylation of the kinetochore component Cep1 induced by DSB caused centromere release from the spindle pole body explaining chromatin movement [68]. Further, it was observed that fixing telomeres to the nuclear periphery limits chromatin movement and that its physical rupture allows additional mobility. In this study, it was proposed that HR was defective and the mobility increase somehow facilitated activation of cell cycle checkpoints. Nonetheless, a wide body of evidence shows that DSBs are mobile in
In an early study, it was observed that chromatin constrain was dependent on Ku80, which suggested that NHEJ machinery rejoins fast the broken ends to limit chromatin mobility (Figure 4) [76].
Further, a report where transgenes were analyzed revealed long-distance movement that was dependent on MRE11 and was also associated with chromosome translocations [77].
DSB movement has been observed at unprotected and damaged telomeres. These DSBs are protected as they are part of the shelterin complex, thus impeding access to the DSB machinery [79]. The shelterin role has been revealed by showing that its depletion causes DSB response activation, and then telomeres are joined by NHEJ, thus inducing telomere fusions [80]. Further, 53BP1 loss reduced telomere end mobility and promoted almost complete absence of telomeric fusions [81]. Consistently with the previous data, it has been shown that this mobility is dependent on the LINC complex, which is known by connecting dynamic microtubules to the interior of the nucleus [82]. ALT (
5.2. Localized movement
3C methodologies have facilitated the chromosome contacts that occur within and between chromosomes. In
6. Effect of DSB response on transcription
Many studies have described posttranslational modifications in histones that can regulate the transcription process near a DSB as part of DDR. Among them, ubiquitylation and SUMOylation modifications have been shown to silence transcription in the vicinity of DSB regions, thus allowing an efficient repair process and preventing RNA polymerase from producing aberrant transcripts. This phenomenon has been characterized in cells whose DSBs have been produced by either exogenous agents or as a part of a programed cell mechanism, like meiosis.
6.1. DSBs, transcription, and ubiquitination in somatic cells
Kruhlak et al. [91] showed for the first time a correlation between DSBs and transcription in somatic mammalian cells. In this study, they observed a decrease in transcription in nucleoli (RNA pol I) after irradiation in an ATM, Nbs1-, and DMC1-dependent manner, and consequently a prolonged and deficient repair. Later, using a reporter system that allows in single cells the visualization of repair factors recruitment, as well as local transcription, an ATM-dependent transcriptional silencing program in cis to DSBs was described. In this study, ATM prevents chromatin decondensation, thus affecting RNA polymerase II elongation at regions distal to DSBs. It was also observed that silencing, at least partially depends on RNF8 and RNF168 (E3 ubiquitin ligases), while its reversal relies on the uH2A USP16 (deubiquitylating enzyme) [92]. This study suggested that H2A ubiquitylation on areas near DSBs is important for efficient recruitment of repair factors. In contrast, deficiency of E3 ligases like RNF8 or RNF168 does not deeply impact in silencing in the context of DSB, suggesting that even though these specific ubiquitylation modifications contribute to DSB silencing, other ATM-dependent events surely cooperate in suppressing transcription [22]. TDP2 is a phosphodiesterase needed for the accurate repair of DSB caused by topoisomerase II (TOP2) abortive activity [93]. TOP2 removes hurdles on the way for efficient transcription and replication such as torsional stress from DNA, by generating intermediate cleavages and binding to the DSB 5′ terminus [94]. Normally, the cleavage and rejoining of DNA strand are transitory processes; however, this may be halted by DNA or RNA polymerases that could convert complexes into abortive DSBs which could activate the DNA repair response [95]. As shown, TDP2 ensures gene transcription from endogenous abortive TOP2 activity. Further, TDP2 has one ubiquitin-associated (UBA) domain, which is able to bind several forms of ubiquitin, thus providing potential multiple biological functions of TDP2 [96].
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