Structure-specific endonucleases (SSEs) have key roles in DNA replication, recombination and repair, and emerging roles in transcription. These enzymes have specificity for DNA secondary structure rather than for sequence, and therefore their activity must be precisely controlled to ensure genome stability. In this Review, we discuss how SSEs are controlled as part of genome maintenance pathways in eukaryotes, with an emphasis on the elaborate mechanisms that regulate the members of the major SSE families — including the xeroderma pigmentosum group F-complementing protein (XPF) and MMS and UV-sensitive protein 81 (MUS81)-dependent nucleases, and the flap endonuclease 1 (FEN1), XPG and XPG-like endonuclease 1 (GEN1) enzymes — during processes such as DNA adduct repair, Holliday junction processing and replication stress. We also discuss newly characterized connections between SSEs and other classes of DNA-remodelling enzymes and cell cycle control machineries, which reveal the importance of SSE scaffolds such as the synthetic lethal of unknown function 4 (SLX4) tumour suppressor for the maintenance of genome stability.
At a glance
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References 15–18 describe the identification of human SLX4 and how it binds multiple proteins and/or complexes that are involved in genome maintenance, which include XPF–ERCC1, SLX1 and MUS81–EME1.
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Describes how the first incision in NER is made by XPF–ERCC1, which is necessary for the second incision that is carried out by XPG.
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Demonstrates that SLX4 is a tumour suppressor in mice, together with detailed biochemical analyses of the stimulation of XPF–ERCC1 by SLX4 on ICL repair intermediates.
- XPF–ERCC1 acts in unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol. Cell 54, 1–12 (2014).
Describes the use of Xenopus laevis oocyte extracts to analyse the timely recruitment of FANCD2, SLX4 and XPF–ERCC1 to DNA during ICL repair.
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Shows that recruitment of FAN1 to ubiquitylated FANCD2 through its UBZ motif is crucial during replication inhibition, but is dispensable for ICL repair. A FAN1 variant from high-risk pancreatic cancer is not recruited to ubiquitylated FANCD2.
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Seminal study about cell cycle control of the Holliday junction resolvases Mus81–Mms4 and Yen1 in meiosis and mitosis in S. cerevisiae, and MUS81–EME1 and GEN1 in mitotic human cells.
, , , &
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Describes the importance of the timely upregulation of Mus81–Mms4 in mitotic cells and the dire consequences if it is constitutively hyperactivate.
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- Cooperative control of Holliday junction resolution and DNA repair by the SLX1 and MUS81–EME1 nucleases. Mol. Cell 52, 1–13 (2013).
References 48 and 49 show that SLX4 controls and coordinates Holliday junction resolution by both SLX1 and MUS81–EME1.
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- Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation. Oncogene 22, 4301–4313 (2003). , &
- Sequential posttranslational modifications program FEN1 degradation during cell-cycle progression. Mol. Cell 47, 444–456 (2012).
Identifies a mechanism that controls the programmed degradation of FEN1 through sequential phosphorylation, sumoylation and ubiquitylation of FEN1.
- Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nat. Chem. Biol. 6, 766–773 (2010). et al.
- Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. Mol. Cell 7, 1221–1231 (2001). et al.
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- The two DNA clamps Rad9/Rad1/Hus1 complex and proliferating cell nuclear antigen differentially regulate flap endonuclease 1 activity. J. Mol. Biol. 353, 980–989 (2005). et al.
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- Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity. EMBO J. 20, 5791–5801 (2001). et al.
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- The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA. Nucleic Acids Res. 33, 6769–6781 (2005). et al.
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- Nucleolar localization and dynamic roles of flap endonuclease 1 in ribosomal DNA replication and damage repair. Mol. Cell. Biol. 28, 4310–4319 (2008). et al.
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- Flap endonuclease 1 limits telomere fragility on the leading strand. J. Biol. Chem. 290, 15133–15145 (2015). et al.
- WRN helicase and FEN-1 form a complex upon replication arrest and together process branchmigrating DNA structures associated with the replication fork. Mol. Biol. Cell 15, 734–750 (2004). et al.
- Wuho is a new member in maintaining genome stability through its interaction with flap endonuclease 1. PLoS Biol. 14, e1002349 (2016).
Identification of WUHO as a positive and negative regulator of the flap and gap endonuclease functions of FEN1, respectively.
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- Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. Mol. Cell 47, 396–409 (2012). et al.
- The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. Mol. Cell 47, 410–421 (2012). , &
- ZRANB3 is a structure-specific ATP-dependent endonuclease involved in replication stress response. Genes Dev. 26, 1558–1572 (2012).
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- Identification of proteins at active, stalled, and collapsed replication forks using isolation of proteins on nascent DNA (iPOND) coupled with mass spectrometry. J. Biol. Chem. 288, 31458–31467 (2013). et al.
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- Structure and specificity of the bacterial cysteine methyltransferase effector NleE suggests a novel substrate in human DNA repair pathway. PLoS Pathog. 10, e1004522 (2014). et al.
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- Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Mol. Cell. Biol. 20, 8758–8766 (2000). et al.
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- Exploring the roles of Mus81–Eme1/Mms4 at perturbed replication forks. DNA Repair 6, 1004–1017 (2007). &
- Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells. EMBO J. 22, 6137–6147 (2003). et al.
- Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis. Mol. Cell. Biol. 25, 7569–7579 (2005). et al.
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- Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response. Oncotarget 6, 37638–37646 (2015). et al.
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- A winged helix domain in human MUS81 binds DNA and modulates the endonuclease activity of MUS81 complexes. Nucleic Acids Res. 41, 9741–9752 (2013). et al.
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Provides evidence of the potentially deleterious effects of Mus81 during replication, especially when not controlled by Cds1.
, , &
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- Wee1 controls genomic stability during replication by regulating the Mus81–Eme1 endonuclease. J. Cell Biol. 194, 567–579 (2011). et al.
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- DNA-repair scaffolds dampen checkpoint signalling by counteracting the adaptor Rad9. Nature 493, 120–124 (2013). , , , &
- The Slx4–Dpb11 scaffold complex: coordinating the response to replication fork stalling in S-phase and the subsequent mitosis. Cell Cycle 14, 488–494 (2015). , &
- Assembly of Slx4 signaling complexes behind DNA replication forks. EMBO J. 34, 2182–2197 (2015). et al.
- A cell cycle-regulated Slx4–Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. Genes Dev. 28, 1604–1619 (2014). et al.
- Dampening DNA damage checkpoint signalling via coordinated BRCT domain interactions. EMBO J. 34, 1704–1717 (2015). , , , &
- Dbf4-dependent kinase (DDK) and the Rtt107 scaffold promote Mus81–Mms4 resolvase activation during mitosis. EMBO J. http://dx.doi.org/10.15252/embj.201694831 (2017). et al.
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- Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297, 599–602 (2002). , &
- Maintaining genome stability at the replication fork. Nat. Rev. Mol. Cell Biol. 11, 208–219 (2010). &
- RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes Dev. 27, 2259–2273 (2013). et al.
- Caenorhabditis elegans HIM-18/SLX-4 interacts with SLX-1 and XPF-1 and maintains genomic integrity in the germline by processing recombination intermediates. PLoS Genet. 5, e1000735 (2009). , , &
- Slx1–Slx4 is a second structure-specific endonuclease functionally redundant with Sgs1–Top3. Genes Dev. 17, 1768–1778 (2003). &
- Slx1–Slx4 are subunits of a structure-specific endonuclease that maintains ribosomal DNA in fission yeast. Mol. Biol. Cell 15, 71–80 (2004). et al.
- Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase. Cell 149, 334–347 (2012). , , &
- The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability. Mol. Cell 57, 123–137 (2015). et al.
- Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. Mol. Cell 57, 108–122 (2015). et al.
- Replication stress activates DNA repair synthesis in mitosis. Nature 528, 1–17 (2015). et al.
- MUS81 promotes common fragile site expression. Nat. Cell Biol. 15, 1001–1007 (2013). et al.
- ERCC1 and MUS81–EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat. Cell Biol. 15, 1008–1015 (2013). , , &
- DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis. J. Cell Biol. 201, 395–408 (2013). et al.
- ERCC1/XPF removes the 3′ overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol. Cell 12, 1489–1498 (2003). et al.
- Telomere recombination requires the MUS81 endonuclease. Nat. Cell Biol. 11, 616–623 (2009). et al.
- ERCC1/XPF protects short telomeres from homologous recombination in Arabidopsis thaliana. PLoS Genet. 5, e1000380 (2009). , , &
- SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Rep. 4, 861–869 (2013). et al.
- Localization-dependent and -independent roles of SLX4 in regulating telomeres. Cell Rep. 4, 853–860 (2013). et al.
- SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic Acids Res. 43, 5912–5923 (2015). et al.
- RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149, 795–806 (2012). , , , &
- The basic N-terminal domain of TRF2 limits recombination endonuclease action at human telomeres. Cell Cycle 13, 2469–2474 (2014). et al.
- TRF2 promotes, remodels and protects telomeric Holliday junctions. EMBO J. 28, 641–651 (2009). et al.
- Nuclease delivery: versatile functions of SLX4/FANCP in genome maintenance. Mol. Cells 37, 569–574 (2014).
- Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia. J. Cell Sci. 127, 2811–2817 (2014). et al.
- Sumoylation of the Rad1 nuclease promotes DNA repair and regulates its DNA association. Nucleic Acids Res. 42, 6393–6404 (2014). et al.
- Phosphorylation of Slx4 by Mec1 and Tel1 regulates the single-strand annealing mode of DNA repair in budding yeast. Mol. Cell. Biol. 27, 6433–6445 (2007). et al.
- A versatile scaffold contributes to damage survival via sumoylation and nuclease interactions. Cell Rep. 9, 143–152 (2014). et al.
- Microarray-based genetic screen defines SAW1, a gene required for Rad1/Rad10-dependent processing of recombination intermediates. Mol. Cell 30, 325–335 (2008). et al.
- Fission yeast Pxd1 promotes proper DNA repair by activating Rad16XPF and inhibiting Dna2. PLoS Biol. 12, e1001946 (2014).
Identifies Pxd1 as a novel nuclease scaffold in fission yeast that differentially regulates Rad16–Swi10 and Dna2 endonucleases.
- SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes Dev. 26, 151–162 (2012). et al.
- FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Nat. Commun. 4, 1423 (2013). et al.
- Histone modifications predispose genome regions to breakage and translocation. Genes Dev. 29, 1393–1402 (2015). , , , &
- NER factors are recruited to active promoters and facilitate chromatin modification for transcription in the absence of exogenous genotoxic attack. Mol. Cell 38, 54–66 (2010). et al.
- Non-catalytic roles for XPG with BRCA1 and BRCA2 in homologous recombination and genome stability. Mol. Cell 61, 535–546 (2016). et al.
- Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell 156, 134–145 (2014). et al.
- H. pylori-induced DNA strand breaks are introduced by nucleotide excision repair endonucleases and promote NF-κB target gene expression. Cell Rep. 13, 70–79 (2015). et al.
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Demonstrates that the scaffold protein Saw1 is a structure-specific DNA-binding protein that targets and activates Rad1–Rad10 during SSA.
- Supplementary information S1 (519 KB)
Conserved families of structure-specific endonucleases
- Supplementary information S2 (207 KB)
Positive and negative regulation of SSEs
- Supplementary information S3 (783 KB)
Controlling the resolution of joint molecules by SSEs in meiosis.
- Supplementary information S4 (238 KB)
Structure-specific endonuclease scaffolds.