Article series: DNA damage

Control of structure-specific endonucleases to maintain genome stability

Journal name:
Nature Reviews Molecular Cell Biology
Volume:
18,
Pages:
315–330
Year published:
DOI:
doi:10.1038/nrm.2016.177
Published online

Abstract

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

Figures

  1. DNA secondary structures processed by structure-specific endonucleases.
    Figure 1: DNA secondary structures processed by structure-specific endonucleases.

    Schematic representation of DNA secondary structures that are processed by structure-specific endonucleases (SSEs). Red arrows indicate DNA cleavage, blue arrows indicate DNA synthesis and green arrows indicate RNA synthesis. Note that the recently described endonucleolytic activity of two orthologous exonucleases, mammalian CtBP-interacting protein (CtIP) and Saccharomyces cerevisiae sporulation in the absence of SPO11 protein 2 (Sae2), is under debate195, 196. D-loop, displacement loop; DNA2, DNA replication ATP-dependent helicase–nuclease 2; EME1, essential meiotic endonuclease 1; ERCC1, excision repair cross-complementing group 1 protein; FAN1, Fanconi-associated nuclease 1; FEN1, flap endonuclease 1; GEN1, XPG-like endonuclease 1; ICL, interstrand crosslink; MRE11, meiotic recombination protein 11; MUS81, MMS and UV-sensitive protein 81; Rad27, radiation-sensitive mutant 27; SLX1, synthetic lethal of unknown function 1; Swi10, mating-type switching protein 10; XPF, xeroderma pigmentosum group F-complementing protein.

  2. Control of structure-specific endonucleases during nucleotide excision repair.
    Figure 2: Control of structure-specific endonucleases during nucleotide excision repair.

    a | Xeroderma pigmentosum group G-complementing protein (XPG) is the first structure-specific endonuclease (SSE) to be recruited to the vicinity of a helix-distorting DNA adduct during nucleotide excision repair (NER). This occurs through its interaction with the transcription initiation factor IIH (TFIIH) complex, which includes the DNA helicases XPB and XPD, and the single strand-binding complex replication protein A (RPA)24. At this stage, XPG appears to fulfil a structural role in the stabilization of a pre-incision complex, as it is catalytically inactive25. Following recruitment of XPG, XPF–excision repair cross-complementing group 1 protein (ERCC1) is recruited through the interaction of ERCC1 with the NER factor XPA, which positions XPF–ERCC1 at the correct junction for cleavage (red arrow) of the damaged strand. Repair synthesis (brown arrow) from the 3′ OH end that is generated by XPF-ERCC1 causes strand displacement and the generation of a 5′ flap, which activates XPG to cut the DNA on the other side of the lesion25. It has been proposed that this sequential action of the two SSEs ensures that XPG cleaves when repair synthesis has passed the lesion and that the newly synthesized strand is ready to be ligated to the 5′ phosphate group that is generated by the XPG incision30. b | Control of XPF–ERCC1 and XPG activity is of critical importance, as they can potentially cut both the damaged and undamaged DNA strands, which can lead to the generation of double-strand breaks and loss of the intervening sequence. DNA Pol, DNA polymerase; PCNA, proliferating cell nuclear antigen.

  3. Controlling the processing of Holliday junctions by structure-specific endonucleases.
    Figure 3: Controlling the processing of Holliday junctions by structure-specific endonucleases.

    a | In Saccharomyces cerevisiae, efficient processing of Holliday junctions during late G2 and mitosis relies on the timely activation of both MMS and UV-sensitive protein 81 (Mus81)–methane methylsulfonate-sensitive protein 4 (Mms4) and crossover junction endodeoxyribonuclease 1 (Yen1) through cycles of phosphorylation (P) and dephosphorylation. Phosphorylation of Mms4 by both Cdc28 and Cdc5 occurs during the G2–M transition and results in catalytic stimulation of Mus81–Mms4 (Refs 39, 42, 43, 130, 197). By contrast, Cdc28-mediated phosphorylation of Yen1 at the G1–S transition keeps it catalytically inactive until anaphase, when it is dephosphorylated by Cdc14 (Refs 50, 51, 52). Furthermore, phosphorylation of Yen1 inactivates its nuclear localization signal (NLS), thereby retaining the protein in the cytoplasm until anaphase. Hyperactivated Holliday junction resolvases are outlined in red. b | In contrast to the cell cycle-dependent activation of Mus81–Mms4, upregulation of Mus81–essential meiotic endonuclease 1 (Eme1) activity in Schizosaccharomyces pombe occurs in response to DNA damage44. Cdc2-mediated phosphorylation primes Eme1 for DNA damage-induced phosphorylation by radiation-sensitive mutant 3 (Rad3). The sequential phosphorylation of Eme1 restricts the catalytic upregulation of Mus81–Eme1 to G2 and only when the DNA damage checkpoint is activated. This control mechanism appears to be crucial for the cell to survive DNA damage that results from loss of the helicase RecQ homologue 1 (Rqh1). c | In human cells, cell cycle-dependent phosphorylation of EME1 by cyclin-dependent kinase 1 (CDK1) and Polo-like kinase 1 (PLK1) correlates with increased Holliday junction resolvase activity of MUS81–EME1 (Ref. 41); it also promotes interaction of MUS81–EME1 with the synthetic lethal of unknown function 4 (SLX4)–SLX1 Holliday junction resolvase. Increased Holliday junction resolution relies on the coordinated action of both nucleases48, 49. Control of XPG-like endonuclease 1 (GEN1) is independent of phosphorylation, but instead relies entirely on a nuclear export signal (NES) that prevents GEN1 from accessing chromosomes until breakdown of the nuclear envelope in mitosis53. The timing of this upregulation of Holliday junction resolvases is thought to provide time for double Holliday junctions to be processed by the RecQ-like helicases, which act in partnership with a type I topoisomerase and accessory factors. The corresponding Sgs1–TopIII–Rmi1, Rqh1–TopIII–Rmi1 and BLM–TOPIII–RMI1–RMI2 complexes are shown for S. cerevisiae (part a), S. pombe (part b) and human cells (part c), respectively. BLM, Bloom syndrome protein; Chk1, checkpoint kinase 1; Rmi1, RecQ-mediated genome instability protein 1; Sgs1, slow growth suppressor 1; TopIII, DNA topoisomerase III.

  4. Function of FEN1 in Okazaki fragment maturation.
    Figure 4: Function of FEN1 in Okazaki fragment maturation.

    A | Okazaki fragment processing by flap endonuclease 1 (FEN1) and DNA replication ATP-dependent helicase–nuclease 2 (DNA2). In part Aa, FEN1 processes a 5′ flap that has not been coated by the single strand-binding complex replication protein A (RPA), but that is long enough to contain the entire portion of DNA synthesized by the low-fidelity DNA polymerase-α (Polα). In part Ab, the acetyltransferase EA1-binding protein p300 (EP300) interacts with and acetylates (Ac) FEN1, thereby reducing its DNA-binding and DNA-processing abilities69. This modification may prevent FEN1 from acting too soon during strand displacement by Polδ, and thus reduce the risk that DNA synthesized by the low-fidelity Polα remains in the genome after Okazaki fragment maturation. In part Ac, the two nuclease-mediated Okazaki fragment processing pathway is shown. EP300 acetylates and stimulates the nuclease DNA2, which converts the long RPA-coated flap into a short flap (arrow 1) that can be processed by FEN1 (arrow 2). The RecQ helicase Bloom syndrome protein (BLM) may enhance the process by stimulating FEN1 activity as well as by promoting strand displacement74. Here, FEN1 is shown unacetylated, but given that Werner syndrome ATP-dependent helicase (WRN) can stimulate acetylated FEN1 (Ref. 78), it is possible that BLM may also stimulate acetylated FEN1. Alternatively, acetylated FEN1 might be deacetylated by an unknown deacetylase. B | Post-translational modifications control FEN1 activity. Phosphorylation (P) of FEN1 by cyclin-dependent kinase 1 (CDK1) inhibits its interaction with proliferating cell nuclear antigen (PCNA), together with promoting sumoylation of FEN1 by an unknown small ubiquitin-related modifier (SUMO) E3 ligase. Sumoylation allows ubiquitylation (Ub) of FEN1 by the ubiquitin E3 ligase pre-mRNA processing factor 19 (PRP19), in association with ubiquitin-activating enzyme E1 (UBE1) and UBE2, which targets FEN1 for proteasomal degradation. Methylation (Me) of FEN1 by the methyltransferase protein Arg N-methyltransferase 5 (PRMT5) inhibits the phosphorylation of FEN1 by CDK1, which thereby promotes the interaction of FEN1 with PCNA and stimulates FEN1 catalytic activity. The identification of a FEN1 demethylating enzyme would aid our understanding of how the balance between methylation and phosphorylation is controlled.

  5. Function of structure-specific endonucleases during replication stress.
    Figure 5: Function of structure-specific endonucleases during replication stress.

    a | Structure-specific endonucleases (SSEs; green) are needed to promote replication fork recovery and progression in conditions of mild replication stress and S phase checkpoint activation (green halo). The precise nature of the secondary structures that are processed during replication stress remains to be determined. A reversed fork is shown as an example (see Fig. 1 for other possible structures). Reversed replication forks and other unusual replication intermediates have been shown by electron microscopy to accumulate in response to replication stress146, 147, 148, 149. MMS and UV-sensitive protein 81 (MUS81) nucleases have important but poorly understood functions at stressed replication forks104, 105, 106, 109, 110, 112, 113, 121, 122, 123, 124. The question mark indicates that there is some debate about which of the essential meiotic endonuclease (EME) proteins, EME1 or EME2, is active in response to mild replication stress. Fanconi-associated nuclease 1 (FAN1) is recruited through its ubiquitin-binding zinc finger motif to stalled replication forks35, whereas zinc finger RAN-binding domain-containing protein 3 (ZRANB3) is recruited to polyubiquitylated proliferating cell nuclear antigen (not shown)95, 96, 97. By contrast, recruitment of MUS81-nucleases is poorly understood. Xeroderma pigmentosum group F-complementing protein (XPF)–excision repair cross-complementing group 1 protein (ERCC1) may also fulfil some functions during mild replication stress in the absence of MUS81 (Ref. 123). Several helicases (purple) can directly modulate the catalytic activity of some of the SSEs, provide them with potential substrates, or unfold secondary structures that are otherwise processed by SSEs. Both of the helicases Werner syndrome ATP-dependent helicase (WRN)76, 77, 78 and Bloom syndrome protein (BLM)74, 75 stimulate flap endonuclease 1 (FEN1). BLM can also stimulate MUS81 (Ref. 125), which itself can stimulate FEN1 (Ref. 91). The dashed arrows indicate that these stimulatory effects have been described in vitro only and that additional work is needed to confirm their relevance in vivo. The stimulation of FEN1 by WRN in vivo is important for the response to replication stress90. The helicase SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 (SMARCAL1) promotes replication fork repair and restart and prevents the accumulation of secondary structures that can be processed by MUS81 nucleases177. b | MUS81 nucleases induce deleterious DNA damage in response to replication stress (red halo) when a functional checkpoint response is absent128, 129, 133, 134, 135, 137, with a prominent contribution by EME2 (Refs 137, 138). Currently, it is not known how MUS81–EME2 activity is controlled. A possible role of cyclin-dependent kinase 2 (CDK2) (Ref. 137) is indicated by a dashed arrow. This is in contrast to CDK1, which phosphorylates EME1 and synthetic lethal of unknown function 4 (SLX4) (Refs 39, 138) and promotes the association of MUS81 with SLX4. F-box DNA helicase 1 (FBH1) increases genome instability following prolonged replication stress by generating DNA secondary structures that are processed in a MUS81- and SLX4-dependent manner178. When ataxia telangiectasia and Rad3-related protein (ATR) is inhibited, the helicase SMARCAL1 also generates secondary structures that lead to replication fork breakage in an SLX4-dependent manner, but it is not known which nucleases contribute to this198. Following ATR inhibition, RING finger protein 4 (RNF4) and Polo-like kinase 1 (PLK1) contribute to replication fork breakdown, which leads to SLX4-dependent cleavage of replication forks. CHK1, checkpoint kinase 1; DSB, DNA double-strand break.

  6. Scaffold protein control of structure-specific endonucleases.
    Figure 6: Scaffold protein control of structure-specific endonucleases.

    a | Synthetic lethal of unknown function 4 (SLX4) controls structure-specific endonucleases (SSEs) by recruiting them to sites of DNA repair and recombination and by stimulating their activity (for a review, see Ref. 170). It can contribute to the coordination of several nucleases within the same pathway, such as MMS and UV-sensitive protein 81 (MUS81)–essential meiotic endonuclease 1 (EME1) and SLX1 in homologous recombination48, 49. SLX4 is recruited to sites of replication-dependent interstrand crosslink (ICL) repair by its first ubiquitin-binding zinc finger (UBZ) motif34, 171, 199, where it recruits and stimulates xeroderma pigmentosum group F-complementing protein (XPF)–excision repair cross-complementing group 1 protein (ERCC1)33, 34. The function of SLX4 during replication stress and in the maintenance of common fragile sites relies on its recruitment to chromatin through small ubiquitin-like modifier (SUMO)-interaction motifs (SIMs)155, 156, which also contribute to its localization at telomeres156. The MUS312–MEI9 interaction-like region (MLR) and the bric-a-brac–tramtrack–broad complex (BTB) domains of SLX4 are needed for its interaction with XPF. The SAFA/B, Acinus and PIAS (SAP) domain and conserved carboxy-terminal domain (CCD) of SLX4 mediate the interaction with MUS81 and SLX1, respectively, and contribute to the coordination and stimulation of both of these SSEs by SLX4 during Holliday junction resolution48, 49. Ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) is another scaffold for XPF–ERCC1 and MUS81–EME1, and it is an ICL sensor that is involved in an SLX4-independent ICL repair pathway37, 38. It is not known whether this ICL repair mechanism relies on replication or not. b | In Saccharomyces cerevisiae, control of the SSEs Rad1–Rad10 and Slx1 relies on the scaffolds Slx4 (top) and single-strand annealing weakened protein 1 (Saw1) (bottom), respectively. In contrast to mammalian SLX4, Slx4 engages in mutually exclusive interactions with Rad1–Rad10 (left) or Slx1 (right)173. Slx4–Slx1 is crucial for ribosomal DNA (rDNA) stability, for which controlled replication pausing is needed to prevent deleterious collisions between the transcription and replication machineries and to initiate recombination mechanisms to control the number of rDNA repeats200. During repair of DNA double-strand breaks by single-strand annealing, Slx4 stimulates the removal of 3′ flaps by Rad1–Rad10 after the nuclease has been recruited by Saw1 (Refs 173, 201). Saw1 is also involved with Rad1–Rad10 in the repair of damaged bases and the removal of protein–DNA adducts174. Slx4 and Saw1 interact directly, but crosstalk between them is also modulated by sumoylation of Saw1 at Lys221 (K221SUMO) by the SUMO E3 ligases SAP and Miz-finger domain-containing protein 1 (Siz1), Siz2 and methyl methanesulfonate-sensitivity protein 21 (Mms21)174. This contributes to the formation of a Saw1–Slx1–Slx4 complex at the expense of the Saw–Rad1–Rad10 complex, and is important to mediate tolerance to high loads of DNA damage. BER, base excision repair. Red arrows indicate cleavage.

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Affiliations

  1. Centre de Recherche en Cancérologie de Marseille, CRCM, CNRS, Aix Marseille Université, INSERM, Institut Paoli-Calmettes, 27 Boulevard Leï Roure, 13009 Marseille, France.

    • Pierre-Marie Dehé &
    • Pierre-Henri L. Gaillard

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The authors declare no competing interests.

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  • Pierre-Marie Dehé

    Pierre-Marie Dehé carried out his doctoral studies in the laboratory of Vincent Géli at the Centre National de la Recherche Scientifique (CNRS) in Marseille, France, on the functional implications of histone 3 Lys4 (H3K4) methylation by the Set1 complex. He then joined Julie Cooper's group at the London Research Institute, Cancer Research UK, London, UK, to study the molecular mechanisms involved in telomere length maintenance. He has been member of the group of Pierre-Henri Gaillard at the Cancer Research Center of Marseille (CRCM), Marseille, France, since 2011. He has been a researcher of the French National Institute of Health and Medical Research (INSERM) since 2013. His research is focused on understanding how structure-specific endonucleases are controlled to maintain genome stability in fission yeast.

  • Pierre-Henri L. Gaillard

    Pierre-Henri L. Gaillard is a research director at the Centre National de la Recherche Scientifique (CNRS), Marseille, France, and group leader at the Cancer Research Center of Marseille (CRCM), Marseille, France. He carried out his graduate work with Geneviève Almouzni and Ethel Moustacchi at the Institut Curie, Paris, France, and his postdoctoral training with Rick Wood at the Imperial Cancer Research Fund, Clare Hall, UK, and Paul Russell at The Scripps Research Institute, La Jolla, California, USA. His laboratory investigates mechanisms that contribute to genome stability, with a focus on those that control structure-specific endonucleases.

Supplementary information

PDF files

  1. Supplementary information S1 (519 KB)

    Conserved families of structure-specific endonucleases

  2. Supplementary information S2 (207 KB)

    Positive and negative regulation of SSEs

  3. Supplementary information S3 (783 KB)

    Controlling the resolution of joint molecules by SSEs in meiosis.

  4. Supplementary information S4 (238 KB)

    Structure-specific endonuclease scaffolds.

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