Summary of the known E3 ubiquitin ligases targeting BER proteins for ubiquitination.
Abstract
Genome integrity is under constant threat from cellular reactive oxygen species generated by endogenous and exogenous mutagens. The base excision repair (BER) pathway consequently plays a crucial role in the repair of DNA base damage, sites of base loss and DNA single strand breaks that can cause genome instability and ultimately the development of human diseases, including premature ageing, neurodegenerative disorders and cancer. Proteins within the base excision repair pathway are increasingly being found to be regulated and controlled by post-translational modifications, and indeed ubiquitination performs a key role in the maintenance of repair protein levels but may also impact on protein activity and cellular localisation. This process is therefore important in maintaining an efficient cellular DNA damage response, and if not accurately controlled, can cause DNA damage accumulation and promote mutagenesis and genomic instability. In this chapter, we will present up-to-date information on the evidence of ubiquitination of base excision repair proteins, the enzymes involved and the molecular and cellular consequences of this process.
Keywords
- DNA repair
- base excision repair
- DNA damage
- ubiquitin
- ubiquitination
1. Introduction
Every human cell per day is thought to generate greater than 10,000 DNA base lesions and single strand breaks (SSBs) due to the instability of the DNA molecule [1]. These are largely created by cellular reactive oxygen species that are generated by hydrolysis, oxidative metabolism and environmental factors, including ionising radiation (IR). Typical sites of damage include sites of base loss (abasic sites), oxidised DNA bases (e.g. 8-oxoguanine and thymine glycol) and SSBs. If this DNA damage is left unrepaired, it can cause mutagenesis and genome instability which are contributors to the development of human diseases, including premature ageing, neurodegenerative disorders and cancer. The base excision repair (BER) pathway was first identified in the 1970s by Tomas Lindahl (co-recipient of the 2015 Nobel Prize in Chemistry), who discovered the existence of a uracil DNA
As Lindahl had shown, the first step of BER is recognition of the specific damaged DNA base by a DNA glycosylase. In fact 11 DNA glycosylases are now known to exist with each removing particular types of DNA base damage [3, 4]. Indeed there are three uracil DNA glycosylase enzymes that recognise uracil lesions (namely uracil DNA glycosylase, UNG; single-strand-selective monofunctional uracil DNA glycosylase, SMUG1; and thymine DNA glycosylase, TDG), one enzyme that recognises alkylated bases (
2. Regulation of BER proteins through ubiquitination
Since BER is the major cellular mechanism for the repair of DNA base damage and SSBs, and thus for the maintenance of genome stability, it is important that this process is maintained and controlled. The most efficient way of achieving this, particularly in responding to fluctuations in the cellular DNA damage environment, is via controlling cellular protein activity, localisation and overall protein levels. Indeed there is a growing list of the various protein post-translational modifications (PTMs) of BER proteins that have been reported to achieve this [15]. However a role for ubiquitination in controlling BER protein levels, and thus cellular BER activity, has been highlighted particularly in the last decade. Polyubiquitination of BER proteins catalysed by specific E3 ubiquitin ligases has been shown to largely control cellular protein levels via degradation by the 26S proteasome, but additionally monoubiquitination has been observed in some instances that can act by compartmentalising BER proteins or controlling BER protein activity. There are also instances of crosstalk between ubiquitination and other PTMs in controlling cellular BER. Below we aim to summarise all of the available evidence highlighting the enzymes and mechanisms involved in the control of BER proteins through ubiquitination.
2.1. Ubiquitination of DNA glycosylases
2.1.1. Uracil DNA glycosylases: UNG, SMUG1, MBD4, TDG
Of the four members of the uracil DNA glycosylases, only UNG, SMUG1 and TDG have been shown to be ubiquitinated by specific E3 ubiquitin ligases. Binding of the human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr to UNG and SMUG1 was shown to induce their ubiquitination-dependent proteasomal degradation following expression in 293T cells. This was thought to be promoted through the E3 ubiquitin ligase scaffold proteins, Cullin 1 (Cul1) and Cullin 4 (Cul4), as Vpr interacts with these ligases along with UNG and SMUG1 following overexpression and immunoprecipitation from 293T cells [16]. Vpr was subsequently shown to bind to damage-specific DNA-binding protein 1 (DDB1), which is another component of Cul4A E3 ubiquitin ligases, that mediates the degradation of UNG in 293T cells [17]. This is thought to be a specific mechanism that allows the HIV virus to regulate the levels of abasic sites in viral reverse transcripts and thus promotes viral replication. Therefore whether UNG and SMUG1 are targeted for ubiquitination during normal cellular processing and for BER is not yet known. The third member of the uracil DNA glycosylase family, TDG, is largely known for being regulated by the small ubiquitin-like modifier (SUMO). TDG was shown to be modified by SUMO-1 and SUMO-2/3 on lysine 330 following immunoprecipitation from HeLa cells, and this reduces the abasic site affinity of TDG [18]. TDG SUMOylation induces a conformational change in the protein which overcomes product inhibition and is thus a mechanism for increasing enzymatic turnover [19, 20]. More recently, and similar to UNG and SMUG1, TDG has been shown to be a target for ubiquitination-dependent degradation by a Cul4-DDB1 associated E3 ubiquitin ligase complex [21, 22]. Specifically, TDG degradation was catalysed by Cul4A-DDB1 in association with the RING finger protein ROC1/RBX1 and Cdt2 (collectively called CRL4Cdt2), in a PCNA-dependent manner. This was discovered both in a
2.1.2. Helix-hairpin-helix (HhH) DNA glycosylases: OGG1, NTH1, MUTYH
The HhH DNA glycosylases are named after the DNA-binding motif which is present in all three members of the family and are OGG1, NTH1 and MUTYH. OGG1 is the major DNA glycosylase targeting 8-oxoguanine DNA base damage and only one report has suggested that it is a target for ubiquitination. Specifically OGG1 was found to be degraded following mild hyperthermia by the E3 ubiquitin ligase C-terminus of Hsc70-interacting protein (CHIP) [24]. CHIP is well known to be involved in protein quality control, by targeting damaged or misfolded proteins for ubiquitination-dependent degradation via interaction with the molecular chaperones Hsc70 and Hsp90 [25], and as will become clear later in this chapter, can target multiple BER proteins for degradation via the proteasome. Degradation of OGG1 by CHIP through heat inactivation in HeLa cells was shown to cause a reduction in the efficiency of repair of oxidised DNA base damage and cell growth inhibition following treatment with a photosensitiser. NTH1 is the second member of the HhH DNA glycosylases that excises oxidised pyrimidines from DNA, including 5-hydroxycytosine and thymine glycol, although there are no current reports that it is directly targeted for ubiquitination. However there is evidence that MUTYH, the third member of the family that specifically removes adenine residues incorrectly incorporated opposite 8-oxoguanine residues during DNA transcription or replication, is ubiquitinated both
2.1.3. Endonuclease VIII-like glycosylases: NEIL1, NEIL2, NEIL3
NEIL1 and NEIL2 both have a broad range substrate specificity that largely covers those of the HhH enzymes OGG1 and NTH1. However, these DNA glycosylases appear more active on single stranded DNA and bubble structures and so may be more important during replication and transcription where these structures are formed [27, 28]. There is also evidence that NEIL1 is active at complex DNA damage sites, where two or more DNA base lesions are formed in close proximity [29, 30], and on telomeric DNA [31]. NEIL3 substrate activity has also proven to be elusive but can similarly act on telomeric DNA [31, 32] and more recent data has described a role for NEIL3 in unhooking of DNA interstrand crosslinks [33]. The only evidence of ubiquitination-dependent regulation of the NEIL DNA glycosylases is through very recent data involving NEIL1. Using an
2.1.4. N-methyl purine glycosylase (MPG)
MPG is a DNA glycosylase that excises alkylated DNA base damage, including 3-methyladenine and 7-methylguanine. There is no current evidence that this enzyme is regulated directly by ubiquitination, although MPG has been reported to interact with the E3 ubiquitin ligases UHRF1 and UHRF2 following overexpression in HEK293 cells, and interacts with UHRF1 in a number of cancer cell lines, including MCF7, HeLa and H1299 [35].
2.2. Ubiquitination of DNA strand break binders/processors
2.2.1. Poly(ADP-ribose) polymerase 1 (PARP-1)
PARP-1 functions in binding to SSBs created during BER, where it mediates poly(ADP-ribosyl)ation of itself and other proteins involved in the repair process and thus promotes the assembly of repair protein complexes, chromatin remodelling and its own eventual dissociation from the DNA. Inhibitors targeting PARP-1 activity have recently been approved for the treatment of BRCA-deficient cancers, through which they cause synthetic lethality. This therapeutic exploitation provides an added incentive to enhance our understanding of the regulation of cellular PARP-1, particularly through ubiquitination.
The first report to show that PARP-1 is ubiquitinated was in mouse embryonic fibroblasts following treatment with the proteasome inhibitor ALLN [36]. PARP-1 ubiquitination was further examined
A third E3 ubiquitin ligase has been identified for PARP-1, namely the checkpoint with forkhead-associated and RING finger domain protein (CHFR), which was shown to polyubiquitinate PARP-1
As multiple E3 ubiquitin ligases have been implicated as effectors of PARP-1 ubiquitination, more research is required to determine which of these are crucially involved in the regulation of steady state PARP-1 levels and which function specifically during BER. It is apparent that PARP-1 regulation is multifaceted, with the added complexity of crosstalk between ubiquitination and other PTMs such as SUMOylation and poly(ADP-ribosyl)ation, therefore it may be some time before the intricacies of this regulation are elucidated.
2.2.2. AP endonuclease I (APE1)
APE1 is the major enzyme targeting abasic sites for incision in human cells, and both an over-abundance and lack of this protein can cause genome instability, so the protein levels must be tightly regulated. APE1 was first shown to be monoubiquitinated within the N-terminus of the protein in HCT116 cells by overexpression of the E3 ubiquitin ligase mouse double minute homologue 2 (MDM2), the major enzyme regulating the p53 tumour suppressor protein [41]. Depletion of MDM2 consequently increased APE1 protein levels, thought to be as a result of reduced ubiquitination-dependent degradation. The same authors then reported that phosphorylation of APE1 at threonine 233 by cyclin-dependent kinase 5 (Cdk5)-enhanced MDM2-dependent ubiquitination of APE1 [42]. Indeed, a phosphomimetic mutant (T233E) of APE1 exhibited augmented ubiquitination following expression in HCT116, SW480 and A549 cells. However MDM2 knockout mouse embryonic fibroblasts expressing the phosphomimetic mutant of APE1 still displayed significant APE1 ubiquitination, demonstrating the existence of other E3 ubiquitin ligases for the protein. In fact utilising an
2.2.3. Polynucleotide kinase phosphatase (PNKP)
PNKP acts to remove the 3′-phosphate group remaining from the actions of NEIL1–3 during BER, but also displays kinase activity for 5′-DNA ends and thus plays a role in the repair of SSBs and double strand breaks. A crosstalk between phosphorylation and ubiquitination has been revealed to be important in the regulation of PNKP protein levels. Phosphorylation catalysed by the ataxia telangiectasia mutated (ATM) protein kinase on serines 114 and 126 of PNKP was shown to stabilise the protein in response to oxidative stress in HCT116 cells, which was mediated through inhibition of ubiquitination, and which was required for efficient SSB repair [45]. An
2.2.4. Flap endonuclease-1 (FEN-1)
FEN-1 acts to remove the flap structures created by Pol δ/ε during long-patch BER.Ubiquitinated FEN-1 has been observed at the end of a sequence of PTMs initiated in late S phase of the cell cycle [47]. It was observed in HeLa cells that phosphorylation of FEN-1 at serine 187, promotes SUMOylation at lysine 168 with SUMO-3, which in turn stimulates polyubiquitination at lysine 354 by the E3 ligase pre-mRNA processing factor 19 (PRP19) to stimulate proteasomal degradation. This was largely discovered through overexpression of individual components within the pathway in HeLa cells, rather than examining endogenous proteins. Furthermore, PRP19 was only characterised in ubiquitinating FEN-1
2.3. Ubiquitination of DNA polymerases
2.3.1. DNA polymerase β (Pol β)
Pol β is the principal polymerase employed within the BER pathway, and primarily acts to insert the correct nucleotide into the repair gap, but also acts as a dRP lyase activity. The stability of Pol β was found to be significantly reduced in XRCC1 deficient EM-C11 cells and in HeLa cells following XRCC1 siRNA treatment, suggesting that Pol β and XRCC1-Lig IIIα form a stable complex that protects Pol β from degradation [48]. The major E3 ubiquitin ligase for Pol β was then revealed through the utilisation of
2.3.2. DNA polymerase λ (Pol λ)
Although Pol β is the chief polymerase in the BER pathway, Pol λ is thought to have a back-up role, specifically in the bypass of 8-oxoguanine lesions and thus avoiding the tendency for the misincorporation of the wrong adenine base opposite the lesion. Initial evidence that Pol λ is regulated by ubiquitination was demonstrated by the observation that a Cdk2/cyclin A phosphorylation defective mutant of Pol λ at threonine 553, was less stable than the wild type protein following expression in either 293T or U2OS cells, and that this was mediated via increased ubiquitination [52]. Phosphorylation of Pol λ was observed most notably in late S and G2 phases of the cell cycle and was thought to stabilise the protein via inhibition of ubiquitination and to allow Pol λ to repair any DNA damage incurred at this stage. The major E3 ubiquitin ligase responsible for Pol λ ubiquitination was subsequently identified using the protein as a substrate in
2.3.3. DNA polymerase δ/ε (Pol δ/ε)
Pol δ and ε participate in long-patch BER by adding multiple complimentary nucleotides into the repair gap vacated by Pol β, thus creating a 5′-flap structure which is a substrate for FEN-1. Pol δ is synthesised in human cells as a heterotetramer of subunits p125, p68, p50 and p12. Using an
2.4. Ubiquitination of DNA ligases
2.4.1. X-ray cross-complementing protein 1 and DNA ligase IIIα (XRCC1-Lig IIIα)
Lig IIIα functions in a stable complex with the scaffold protein XRCC1 to seal the nick in the DNA backbone to complete the BER process. Lig IIIα itself been shown to undergo ubiquitination in two separate reports. In the first, CHIP was demonstrated as an E3 ubiquitin ligase for Lig IIIα
2.4.2. DNA ligase I (Lig I)
Lig I is employed during long-patch BER, but is also involved in DNA replication. The only reported evidence of Lig I ubiquitination is through the Cul4A-DDB1 E3 ubiquitin ligase complex [58]. Overexpression and immunoprecipitation of Lig I from 293T cells revealed that lysine 376, and possibly lysine 79 and 192, were potential ubiquitination sites and that a lysine to arginine mutant of Lig I at four sites (79, 192, 226 and 376) was more stable than the wild type protein to degradation through serum starvation. Lig I was then demonstrated to interact with and to be ubiquitinated
2.5. Summary and future outlook
An increasing amount of evidence is strengthening the fact that BER is carefully regulated and controlled by ubiquitination. This largely appears to be a mechanism for controlling cellular BER protein levels via the 26S proteasome and therefore plays an important role in supressing DNA damage accumulation and coordinating an efficient cellular DNA damage response. In this Chapter we have presented evidence that the majority of BER proteins have been shown
E3 ubiquitin ligase | BER protein | Reference |
---|---|---|
CHIP | Lig III | [48] |
OGG1 | [24] | |
Pol β | [48] | |
Pol λ | [54] | |
XRCC1 | [48] | |
Cul1 | SMUG1 | [16] |
UNG | [16] | |
Cul4 | Lig I | [58] |
PNKP | [45] | |
SMUG1 | [16] | |
TDG | [21, 22] | |
UNG | [16] | |
Iduna/RNF146 | Lig III | [38] |
PARP-1 | [38] | |
XRCC1 | [38] | |
MDM2 | APE1 | [41] |
Mule | MUTYH | [26] |
NEIL1 | [34] | |
Pol β | [49] | |
Pol λ | [53] | |
RNF8 | Pol δ | [55] |
TRIM26 | NEIL1 | [34] |
UBR3 | APE1 | [43] |
Unknown | MBD4 | |
NEIL2 | ||
NEIL3 | ||
NTH1 | ||
Pol ε |
In addition to discovering the molecular details for regulating cellular BER, research into the associations of these and the development of human diseases, including premature ageing, neurodegenerative diseases and cancer is essential. It is understood that BER protein levels are frequently misregulated in these diseases although whether defective ubiquitination is contributory to this effect is largely unknown and understudied. This information may also uncover novel therapeutic strategies for the treatment of specific diseases. Indeed the BER pathway is known to be an attractive therapeutic target, which is exemplified by the success of PARP inhibitors in the treatment of BRCA-deficient breast cancers which block BER and cause synthetic lethality due to the inability of these cells to process DNA double strand breaks. It is therefore entirely possible that the discovery of E3 ubiquitin ligases or deubiquitination enzymes targeting BER proteins may provide novel cellular targets for drugs or small molecule inhibitors which can be used in combination with radiotherapy and/or chemotherapy for treatment of diseases, such as cancer.
Acknowledgments
Dr. Jason Parsons is currently supported by funding from North West Cancer Research (CR972, CR1016, CR1074 and CR1145) and by the Medical Research Council via a New Investigator Research Grant (MR/M000354/1).
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