Joint Molecule Resolution Requires the Redundant Activities of MUS-81 and XPF-1 during Meiosis

English version České info

The generation and resolution of joint molecule recombination intermediates is required to ensure bipolar chromosome segregation during meiosis. During wild type meiosis in Caenorhabditis elegans, SPO-11-generated double stranded breaks are resolved to generate a single crossover per bivalent and the remaining recombination intermediates are resolved as noncrossovers. We discovered that early recombination intermediates are limited by the C. elegans BLM ortholog, HIM-6, and in the absence of HIM-6 by the structure specific endonuclease MUS-81. In the absence of both MUS-81 and HIM-6, recombination intermediates persist, leading to chromosome breakage at diakinesis and inviable embryos. MUS-81 has an additional role in resolving late recombination intermediates in C. elegans. mus-81 mutants exhibited reduced crossover recombination frequencies suggesting that MUS-81 is required to generate a subset of meiotic crossovers. Similarly, the Mus81-related endonuclease XPF-1 is also required for a subset of meiotic crossovers. Although C. elegans gen-1 mutants have no detectable meiotic defect either alone or in combination with him-6, mus-81 or xpf-1 mutations, mus-81;xpf-1 double mutants are synthetic lethal. While mus-81;xpf-1 double mutants are proficient for the processing of early recombination intermediates, they exhibit defects in the post-pachytene chromosome reorganization and the asymmetric disassembly of the synaptonemal complex, presumably triggered by crossovers or crossover precursors. Consistent with a defect in resolving late recombination intermediates, mus-81; xpf-1 diakinetic bivalents are aberrant with fine DNA bridges visible between two distinct DAPI staining bodies. We were able to suppress the aberrant bivalent phenotype by microinjection of activated human GEN1 protein, which can cleave Holliday junctions, suggesting that the DNA bridges in mus-81; xpf-1 diakinetic oocytes are unresolved Holliday junctions. We propose that the MUS-81 and XPF-1 endonucleases act redundantly to process late recombination intermediates to form crossovers during C. elegans meiosis.

Vyšlo v časopise: Joint Molecule Resolution Requires the Redundant Activities of MUS-81 and XPF-1 during Meiosis. PLoS Genet 9(7): e32767. doi:10.1371/journal.pgen.1003582
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003582

Souhrn

Zdroje

1. HeyerWD, EhmsenKT, LiuJ (2010) Regulation of homologous recombination in eukaryotes. Annu Rev Genet 44: 113–139.

2. JessopL, RockmillB, RoederGS, LichtenM (2006) Meiotic chromosome synapsis-promoting proteins antagonize the anti-crossover activity of Sgs1. PLoS Genet 2(9): e155.

3. OhSD, LaoJP, HwangPY, TaylorAF, SmithGR, et al. (2007) BLM ortholog, Sgs1, prevents aberrant crossing-over by suppressing formation of multichromatid joint molecules. Cell 130(2): 259–272.

4. ArguesoJL, WanatJ, GemiciZ, AlaniE (2004) Competing crossover pathways act during meiosis in Saccharomyces cerevisiae. Genetics 168(4): 1805–1816.

5. de los SantosT, HunterN, LeeC, LarkinB, LoidlJ, et al. (2003) The Mus81/Mms4 endonuclease acts independently of double-Holliday junction resolution to promote a distinct subset of crossovers during meiosis in budding yeast. Genetics 164(1): 81–94.

6. OsmanF, DixonJ, DoeCL, WhitbyMC (2003) Generating crossovers by resolution of nicked Holliday junctions: A role for Mus81-Eme1 in meiosis. Mol Cell 12(3): 761–774.

7. BoddyMN, GaillardPH, McDonaldWH, ShanahanP, YatesJR3rd, et al. (2001) Mus81-Eme1 are essential components of a Holliday junction resolvase. Cell 107(4): 537–548.

8. LorenzA, WestSC, WhitbyMC (2010) The human Holliday junction resolvase GEN1 rescues the meiotic phenotype of a Schizosaccharomyces pombe mus81 mutant. Nucleic Acids Res 38(6): 1866–1873.

9. BoddyMN, Lopez-GironaA, ShanahanP, InterthalH, HeyerWD, et al. (2000) Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Mol Cell Biol 20(23): 8758–8766.

10. ZakharyevichK, TangS, MaY, HunterN (2012) Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase. Cell 149(2): 334–347.

11. OhSD, LaoJP, TaylorAF, SmithGR, HunterN (2008) RecQ helicase, Sgs1, and XPF family endonuclease, Mus81-Mms4, resolve aberrant joint molecules during meiotic recombination. Mol Cell 31(3): 324–336.

12. JessopL, LichtenM (2008) Mus81/Mms4 endonuclease and Sgs1 helicase collaborate to ensure proper recombination intermediate metabolism during meiosis. Mol Cell 31(3): 313–323.

13. De MuytA, JessopL, KolarE, SourirajanA, ChenJ, et al. (2012) BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism. Mol Cell 46(1): 43–53.

14. MatosJ, BlancoMG, MaslenS, SkehelJM, WestSC (2011) Regulatory control of the resolution of DNA recombination intermediates during meiosis and mitosis. Cell 147(1): 158–172.

15. TrowbridgeK, McKimK, BrillSJ, SekelskyJ (2007) Synthetic lethality of Drosophila in the absence of the MUS81 endonuclease and the DmBlm helicase is associated with elevated apoptosis. Genetics 176(4): 1993–2001.

16. YildizO, MajumderS, KramerB, SekelskyJJ (2002) Drosophila MUS312 interacts with the nucleotide excision repair endonuclease MEI-9 to generate meiotic crossovers. Mol Cell 10(6): 1503–1509.

17. McPhersonJP, LemmersB, ChahwanR, PamidiA, MigonE, et al. (2004) Involvement of mammalian Mus81 in genome integrity and tumor suppression. Science 304(5678): 1822–1826.

18. DendougaN, GaoH, MoecharsD, JanicotM, VialardJ, et al. (2005) Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis. Mol Cell Biol 25(17): 7569–7579.

19. HollowayJK, BoothJ, EdelmannW, McGowanCH, CohenPE (2008) MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. PLoS Genet 4(9): e1000186.

20. HsiaKT, MillarMR, KingS, SelfridgeJ, RedheadNJ, et al. (2003) DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Development 130(2): 369–378.

21. HollowayJK, MohanS, BalmusG, SunX, ModzelewskiA, et al. (2011) Mammalian BTBD12 (SLX4) protects against genomic instability during mammalian spermatogenesis. PLoS Genet 7(6): e1002094.

22. ZalevskyJ, MacQueenAJ, DuffyJB, KemphuesKJ, VilleneuveAM (1999) Crossing over during Caenorhabditis elegans meiosis requires a conserved MutS-based pathway that is partially dispensable in budding yeast. Genetics 153(3): 1271–1283.

23. YoudsJL, MetsDG, McIlwraithMJ, MartinJS, WardJD, et al. (2010) RTEL-1 enforces meiotic crossover interference and homeostasis. Science 327(5970): 1254–1258.

24. SaitoTT, YoudsJL, BoultonSJ, ColaiacovoMP (2009) 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(11): e1000735.

25. BaillyAP, FreemanA, HallJ, DeclaisAC, AlpiA, et al. (2010) The Caenorhabditis elegans homolog of Gen1/Yen1 resolvases links DNA damage signaling to DNA double-strand break repair. PLoS Genet 6(7): e1001025.

26. WardJD, BarberLJ, PetalcorinMI, YanowitzJ, BoultonSJ (2007) Replication blocking lesions present a unique substrate for homologous recombination. EMBO J 26(14): 3384–3396.

27. GartnerA, MilsteinS, AhmedS, HodgkinJ, HengartnerMO (2000) A conserved checkpoint pathway mediates DNA damage–induced apoptosis and cell cycle arrest in C. elegans. Mol Cell 5(3): 435–443.

28. BhallaN, DernburgAF (2005) A conserved checkpoint monitors meiotic chromosome synapsis in Caenorhabditis elegans. Science 310(5754): 1683–1686.

29. EllisHM, HorvitzHR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44(6): 817–829.

30. MullenJR, KaliramanV, IbrahimSS, BrillSJ (2001) Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae. Genetics 157 (1): 103–118.

31. KaliramanV, MullenJR, FrickeWM, Bastin-ShanowerSA, BrillSJ (2001) Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease. Genes Dev 15(20): 2730–2740.

32. WickyC, AlpiA, PassannanteM, RoseA, GartnerA, et al. (2004) Multiple genetic pathways involving the Caenorhabditis elegans Bloom's syndrome genes him-6, rad-51, and top-3 are needed to maintain genome stability in the germ line. Mol Cell Biol 24(11): 5016–5027.

33. AgostinhoA, MeierB, SonnevilleR, HagutM, WoglarA, et al. (2013) Combinatorial regulation of meiotic Holliday junction resolution in C. elegans by him-6/blooms, slx-4 and slx-1, mus-81 and xpf-1 nucleases. PLoS Genet 9: e1003591.

34. SaitoTT, LuiDY, KimH, MeyerK, ColaiacovoMP (2013) Interplay between structure-specific endonucleases for crossover control during Caneorhabditis elegans meiosis. PLoS Genet 9: e1003586.

35. BhallaN, WynneDJ, JantschV, DernburgAF (2008) ZHP-3 acts at crossovers to couple meiotic recombination with synaptonemal complex disassembly and bivalent formation in C. elegans. PLoS Genet 4(10): e1000235.

36. HoCK, MazonG, LamAF, SymingtonLS (2010) Mus81 and Yen1 promote reciprocal exchange during mitotic recombination to maintain genome integrity in budding yeast. Mol Cell 40(6): 988–1000.

37. TayYD, WuL (2010) Overlapping roles for Yen1 and Mus81 in cellular Holliday junction processing. J Biol Chem 285(15): 11427–11432.

38. BlancoMG, MatosJ, RassU, IpSC, WestSC (2010) Functional overlap between the structure-specific nucleases Yen1 and Mus81-Mms4 for DNA-damage repair in S. cerevisiae. DNA Repair (Amst) 9(4): 394–402.

39. HodgkinJ, HorvitzHR, BrennerS (1979) Nondisjunction mutants of the nematode Caenorhabditis elegans. Genetics 91(1): 67–94.

40. NabeshimaK, VilleneuveAM, ColaiacovoMP (2005) Crossing over is coupled to late meiotic prophase bivalent differentiation through asymmetric disassembly of the SC. J Cell Biol 168(5): 683–689.

41. GoodyerW, KaitnaS, CouteauF, WardJD, BoultonSJ, et al. (2008) HTP-3 links DSB formation with homolog pairing and crossing over during C. elegans meiosis. Dev Cell 14(2): 263–274.

42. IpSC, RassU, BlancoMG, FlynnHR, SkehelJM, et al. (2008) Identification of Holliday junction resolvases from humans and yeast. Nature 456(7220): 357–361.

43. KleinHL, SymingtonLS (2009) Breaking up just got easier to do. Cell 138(1): 20–22.

44. NottkeAC, Beese-SimsSE, PantalenaLF, ReinkeV, ShiY, et al. (2011) SPR-5 is a histone H3K4 demethylase with a role in meiotic double-strand break repair. Proc Natl Acad Sci U S A 108(31): 12805–12810.

45. RosuS, LibudaDE, VilleneuveAM (2011) Robust crossover assurance and regulated interhomolog access maintain meiotic crossover number. Science 3346060(): 1286–1289.

46. SaitoTT, MohideenF, MeyerK, HarperJW, ColaiacovoMP (2012) SLX-1 is required for maintaining genomic integrity and promoting meiotic noncrossovers in the Caenorhabditis elegans germline. PLoS Genet 8(8): e1002888.

47. BarberLJ, YoudsJL, WardJD, McIlwraithMJ, O'NeilNJ, et al. (2008) RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135(2): 261–271.

48. ZetkaMC, RoseAM (1995) Mutant rec-1 eliminates the meiotic pattern of crossing over in Caenorhabditis elegans. Genetics 141(4): 1339–1349.

49. HillersKJ, VilleneuveAM (2003) Chromosome-wide control of meiotic crossing over in C. elegans. Curr Biol 13(18): 1641–1647.

50. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77(1): 71–94.

51. CrowEL, GardnerRS (1959) Confidence intervals for the expectation of a poisson variable. Biometrika 28: 46–62.