Mammalian BTBD12 (SLX4) Protects against Genomic Instability during Mammalian Spermatogenesis
The mammalian ortholog of yeast Slx4, BTBD12, is an ATM substrate that functions as a scaffold for various DNA repair activities. Mutations of human BTBD12 have been reported in a new sub-type of Fanconi anemia patients. Recent studies have implicated the fly and worm orthologs, MUS312 and HIM-18, in the regulation of meiotic crossovers arising from double-strand break (DSB) initiating events and also in genome stability prior to meiosis. Using a Btbd12 mutant mouse, we analyzed the role of BTBD12 in mammalian gametogenesis. BTBD12 localizes to pre-meiotic spermatogonia and to meiotic spermatocytes in wildtype males. Btbd12 mutant mice have less than 15% normal spermatozoa and are subfertile. Loss of BTBD12 during embryogenesis results in impaired primordial germ cell proliferation and increased apoptosis, which reduces the spermatogonial pool in the early postnatal testis. During prophase I, DSBs initiate normally in Btbd12 mutant animals. However, DSB repair is delayed or impeded, resulting in persistent γH2AX and RAD51, and the choice of repair pathway may be altered, resulting in elevated MLH1/MLH3 focus numbers at pachynema. The result is an increase in apoptosis through prophase I and beyond. Unlike yeast Slx4, therefore, BTBD12 appears to function in meiotic prophase I, possibly during the recombination events that lead to the production of crossovers. In line with its expected regulation by ATM kinase, BTBD12 protein is reduced in the testis of Atm−/− males, and Btbd12 mutant mice exhibit increased genomic instability in the form of elevated blood cell micronucleus formation similar to that seen in Atm−/− males. Taken together, these data indicate that BTBD12 functions throughout gametogenesis to maintain genome stability, possibly by co-ordinating repair processes and/or by linking DNA repair events to the cell cycle via ATM.
Vyšlo v časopise:
Mammalian BTBD12 (SLX4) Protects against Genomic Instability during Mammalian Spermatogenesis. PLoS Genet 7(6): e32767. doi:10.1371/journal.pgen.1002094
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002094
Souhrn
The mammalian ortholog of yeast Slx4, BTBD12, is an ATM substrate that functions as a scaffold for various DNA repair activities. Mutations of human BTBD12 have been reported in a new sub-type of Fanconi anemia patients. Recent studies have implicated the fly and worm orthologs, MUS312 and HIM-18, in the regulation of meiotic crossovers arising from double-strand break (DSB) initiating events and also in genome stability prior to meiosis. Using a Btbd12 mutant mouse, we analyzed the role of BTBD12 in mammalian gametogenesis. BTBD12 localizes to pre-meiotic spermatogonia and to meiotic spermatocytes in wildtype males. Btbd12 mutant mice have less than 15% normal spermatozoa and are subfertile. Loss of BTBD12 during embryogenesis results in impaired primordial germ cell proliferation and increased apoptosis, which reduces the spermatogonial pool in the early postnatal testis. During prophase I, DSBs initiate normally in Btbd12 mutant animals. However, DSB repair is delayed or impeded, resulting in persistent γH2AX and RAD51, and the choice of repair pathway may be altered, resulting in elevated MLH1/MLH3 focus numbers at pachynema. The result is an increase in apoptosis through prophase I and beyond. Unlike yeast Slx4, therefore, BTBD12 appears to function in meiotic prophase I, possibly during the recombination events that lead to the production of crossovers. In line with its expected regulation by ATM kinase, BTBD12 protein is reduced in the testis of Atm−/− males, and Btbd12 mutant mice exhibit increased genomic instability in the form of elevated blood cell micronucleus formation similar to that seen in Atm−/− males. Taken together, these data indicate that BTBD12 functions throughout gametogenesis to maintain genome stability, possibly by co-ordinating repair processes and/or by linking DNA repair events to the cell cycle via ATM.
Zdroje
1. MullenJRKaliramanVIbrahimSSBrillSJ 2001 Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae. Genetics 157 103 118
2. FrickeWMBrillSJ 2003 Slx1–Slx4 is a second structure-specific endonuclease functionally redundant with Sgs1-Top3. Genes Dev 17 1768 1778
3. LiFDongJPanXOumJHBoekeJD 2008 Microarray-based genetic screen defines SAW1, a gene required for Rad1/Rad10-dependent processing of recombination intermediates. Mol Cell 30 325 335
4. FlottSAlabertCTohGWTothRSugawaraN 2007 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
5. FlottSRouseJ 2005 Slx4 becomes phosphorylated after DNA damage in a Mec1/Tel1-dependent manner and is required for repair of DNA alkylation damage. Biochem J 391 325 333
6. ChangMBellaouiMBooneCBrownGW 2002 A genome-wide screen for methyl methanesulfonate-sensitive mutants reveals genes required for S phase progression in the presence of DNA damage. Proc Natl Acad Sci U S A 99 16934 16939
7. FekairiSScaglioneSChahwanCTaylorERTissierA 2009 Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell 138 78 89
8. SvendsenJMSmogorzewskaASowaMEO'ConnellBCGygiSP 2009 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 138 63 77
9. AndersenSLBergstralhDTKohlKPLaRocqueJRMooreCB 2009 Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structure-specific endonucleases in DNA repair and recombination. Mol Cell 35 128 135
10. MunozIMHainKDeclaisACGardinerMTohGW 2009 Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol Cell 35 116 127
11. MatsuokaSBallifBASmogorzewskaAMcDonaldER3rdHurovKE 2007 ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316 1160 1166
12. StoepkerCHainKSchusterBHilhorst-HofsteeYRooimansMA 2011 SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet
13. SaitoTTYoudsJLBoultonSJColaiacovoMP 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 e1000735 doi:10.1371/journal.pgen.1000735
14. YildizOMajumderSKramerBSekelskyJJ 2002 Drosophila MUS312 interacts with the nucleotide excision repair endonuclease MEI-9 to generate meiotic crossovers. Mol Cell 10 1503 1509
15. KeeneySGirouxCNKlecknerN 1997 Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88 375 384
16. NealeMJPanJKeeneyS 2005 Endonucleolytic processing of covalent protein-linked DNA double-strand breaks. Nature 436 1053 1057
17. HandelMASchimentiJC 2010 Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11 124 136
18. de los SantosTHunterNLeeCLarkinBLoidlJ 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 81 94
19. BornerGVKlecknerNHunterN 2004 Crossover/noncrossover differentiation, synaptonemal complex formation, and regulatory surveillance at the leptotene/zygotene transition of meiosis. Cell 117 29 45
20. OhSDLaoJPTaylorAFSmithGRHunterN 2008 RecQ helicase, Sgs1, and XPF family endonuclease, Mus81-Mms4, resolve aberrant joint molecules during meiotic recombination. Mol Cell 31 324 336
21. JessopLLichtenM 2008 Mus81/Mms4 endonuclease and Sgs1 helicase collaborate to ensure proper recombination intermediate metabolism during meiosis. Mol Cell 31 313 323
22. OhSDLaoJPHwangPYTaylorAFSmithGR 2007 BLM ortholog, Sgs1, prevents aberrant crossing-over by suppressing formation of multichromatid joint molecules. Cell 130 259 272
23. JessopLRockmillBRoederGSLichtenM 2006 Meiotic chromosome synapsis-promoting proteins antagonize the anti-crossover activity of sgs1. PLoS Genet 2 e155 doi:10.1371/journal.pgen.0020155
24. EdelmannWCohenPEKaneMLauKMorrowB 1996 Meiotic pachytene arrest in MLH1-deficient mice. Cell 85 1125 1134
25. LipkinSMMoensPBWangVLenziMShanmugarajahD 2002 Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31 385 390
26. KolasNKSvetlanovALenziMLMacalusoFPLipkinSM 2005 Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I. J Cell Biol 171 447 458
27. SvetlanovABaudatFCohenPEde MassyB 2008 Distinct Functions of MLH3 at Recombination Hot Spots in the Mouse. Genetics 178 1937 1945
28. HollowayJKBoothJEdelmannWMcGowanCHCohenPE 2008 MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. PLoS Genet 4 e1000186 doi:10.1371/journal.pgen.1000186
29. SvendsenJMHarperJW 2010 GEN1/Yen1 and the SLX4 complex: Solutions to the problem of Holliday junction resolution. Genes Dev 24 521 536
30. CrossanGPvan der WeydenLRosadoIVLangevinFGaillardPH 2011 Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nat Genet
31. BarchiMRoigIDi GiacomoMde RooijDGKeeneyS 2008 ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes. PLoS Genet 4 e1000076 doi:10.1371/journal.pgen.1000076
32. BellaniMARomanienkoPJCairattiDACamerini-OteroRD 2005 SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm−/− spermatocytes. J Cell Sci 118 3233 3245
33. DerheimerFAKastanMB 2010 Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Lett 584 3675 3681
34. DertingerSDTorousDKTometskoKR 1996 Simple and reliable enumeration of micronucleated reticulocytes with a single-laser flow cytometer. Mutat Res 371 283 292
35. LevittPSZhuMCassanoAYazinskiSALiuH 2007 Genome maintenance defects in cultured cells and mice following partial inactivation of the essential cell cycle checkpoint gene Hus1. Mol Cell Biol 27 2189 2201
36. ShimaNHartfordSADuffyTWilsonLASchimentiKJ 2003 Phenotype-based identification of mouse chromosome instability mutants. Genetics 163 1031 1040
37. WesternPSMilesDCvan den BergenJABurtonMSinclairAH 2008 Dynamic regulation of mitotic arrest in fetal male germ cells. Stem Cells 26 339 347
38. OrthJM 1982 Proliferation of Sertoli cells in fetal and postnatal rats: a quantitative autoradiographic study. Anat Rec 203 485 492
39. OrthJMJesterWFLiLHLaslettAL 2000 Gonocyte-Sertoli cell interactions during development of the neonatal rodent testis. Curr Top Dev Biol 50 103 124
40. MahadevaiahSKTurnerJMBaudatFRogakouEPde BoerP 2001 Recombinational DNA double-strand breaks in mice precede synapsis. Nat Genet 27 271 276
41. Fernandez-CapetilloOMahadevaiahSKCelesteARomanienkoPJCamerini-OteroRD 2003 H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 4 497 508
42. HondaYTojoMMatsuzakiKAnanTMatsumotoM 2002 Cooperation of HECT-domain ubiquitin ligase hHYD and DNA topoisomerase II-binding protein for DNA damage response. J Biol Chem 277 3599 3605
43. YamaneKWuXChenJ 2002 A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Mol Cell Biol 22 555 566
44. MordesDAGlickGGZhaoRCortezD 2008 TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev 22 1478 1489
45. Parrilla-CastellarERKarnitzLM 2003 Cut5 is required for the binding of Atr and DNA polymerase alpha to genotoxin-damaged chromatin. J Biol Chem 278 45507 45511
46. BurrowsAEElledgeSJ 2008 How ATR turns on: TopBP1 goes on ATRIP with ATR. Genes Dev 22 1416 1421
47. PereraDPerez-HidalgoLMoensPBReiniKLakinN 2004 TopBP1 and ATR colocalization at meiotic chromosomes: role of TopBP1/Cut5 in the meiotic recombination checkpoint. Mol Biol Cell 15 1568 1579
48. WangTFKlecknerNHunterN 1999 Functional specificity of MutL homologs in yeast: evidence for three Mlh1-based heterocomplexes with distinct roles during meiosis in recombination and mismatch correction. Proc Natl Acad Sci U S A 96 13914 13919
49. HollingsworthNMPonteLHalseyC 1995 MSH5, a novel MutS homolog, facilitates meiotic reciprocal recombination between homologs in Saccharomyces cerevisiae but not mismatch repair. Genes Dev 9 1728 1739
50. HunterNBortsRH 1997 Mlh1 is unique among mismatch repair proteins in its ability to promote crossing-over during meiosis. Genes Dev 11 1573 1582
51. Santucci-DarmaninSWalpitaDLespinasseFDesnuelleCAshleyT 2000 MSH4 acts in conjunction with MLH1 during mammalian meiosis. Faseb J 14 1539 1547
52. Ross-MacdonaldPRoederGS 1994 Mutation of a meiosis-specific MutS homolog decreases crossing over but not mismatch correction. Cell 79 1069 1080
53. EdelmannWCohenPEKneitzBWinandNLiaM 1999 Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nature Genetics 21 123 127
54. KneitzBCohenPEAvdievichEZhuLKaneMF 2000 MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev 14 1085 1097
55. OhouoPYBastos de OliveiraFMAlmeidaBSSmolkaMB 2010 DNA damage signaling recruits the Rtt107-Slx4 scaffolds via Dpb11 to mediate replication stress response. Mol Cell 39 300 306
56. Navadgi-PatilVMBurgersPM 2008 Yeast DNA replication protein Dpb11 activates the Mec1/ATR checkpoint kinase. J Biol Chem 283 35853 35859
57. BarlowCLiyanageMMoensPBTarsounasMNagashimaK 1998 Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125 4007 4017
58. AshleyTWestphalCPlug-de MaggioAde RooijDG 2004 The mammalian mid-pachytene checkpoint: meiotic arrest in spermatocytes with a mutation in Atm alone or in combination with a Trp53 (p53) or Cdkn1a (p21/cip1) mutation. Cytogenet Genome Res 107 256 262
59. HoughtalingSTimmersCNollMFinegoldMJJonesSN 2003 Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes Dev 17 2021 2035
60. ChengNCvan de VrugtHJvan der ValkMAOostraABKrimpenfortP 2000 Mice with a targeted disruption of the Fanconi anemia homolog Fanca. Hum Mol Genet 9 1805 1811
61. AgoulnikAILuBZhuQTruongCTyMT 2002 A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd. Hum Mol Genet 11 3047 3053
62. LawsonKAHageWJ 1994 Clonal analysis of the origin of primordial germ cells in the mouse. Ciba Found Symp 182 68 84; discussion 84–91
63. WilhelmDPalmerSKoopmanP 2007 Sex determination and gonadal development in mammals. Physiol Rev 87 1 28
64. TakuboKHiraoAOhmuraMAzumaMAraiF 2006 Premeiotic germ cell defect in seminiferous tubules of Atm-null testis. Biochem Biophys Res Commun 351 993 998
65. LuBBishopCE 2003 Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia. Biol Reprod 69 161 168
66. HsiaKTMillarMRKingSSelfridgeJRedheadNJ 2003 DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Development 130 369 378
67. PittmanDLCobbJSchimentiKJWilsonLACooperDM 1998 Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol Cell 1 697 705
68. RadfordSJGoleyEBaxterKMcMahanSSekelskyJ 2005 Drosophila ERCC1 is required for a subset of MEI-9-dependent meiotic crossovers. Genetics 170 1737 1745
69. RadfordSJMcMahanSBlantonHLSekelskyJ 2007 Heteroduplex DNA in meiotic recombination in Drosophila mei-9 mutants. Genetics 176 63 72
70. TrowbridgeKMcKimKBrillSJSekelskyJ 2007 Synthetic lethality of Drosophila in the absence of the MUS81 endonuclease and the DmBlm helicase is associated with elevated apoptosis. Genetics 176 1993 2001
71. RouseJ 2009 Control of genome stability by SLX protein complexes. Biochem Soc Trans 37 495 510
72. HollowayJKMorelliMABorstPLCohenPE 2010 Mammalian BLM helicase is critical for integrating multiple pathways of meiotic recombination. J Cell Biol 188 779 789
73. LyndakerAMGoldfarbTAlaniE 2008 Mutants defective in Rad1-Rad10-Slx4 exhibit a unique pattern of viability during mating-type switching in Saccharomyces cerevisiae. Genetics 179 1807 1821
74. IpSCRassUBlancoMGFlynnHRSkehelJM 2008 Identification of Holliday junction resolvases from humans and yeast. Nature 456 357 361
75. CoulonSGaillardPHChahwanCMcDonaldWHYatesJR3rd 2004 Slx1-Slx4 are subunits of a structure-specific endonuclease that maintains ribosomal DNA in fission yeast. Mol Biol Cell 15 71 80
76. EdelmannWCohenPEKneitzBWinandNLiaM 1999 Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet 21 123 127
77. WangDEndersGC 1996 Expression of a specific mouse germ cell nuclear antigen (GCNA1) by early embryonic testicular teratoma cells in 129/Sv-Sl/+ mice. Cancer Lett 100 31 36
78. WoodsLMHodgesCABaartEBakerSMLiskayRM 1999 Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice. Journal of Cell Biology 145 1395 1406
79. HodgesCALeMaire-AdkinsRHuntPA 2001 Coordinating the segregation of sister chromatids during the first meiotic division: evidence for sexual dimorphism. J Cell Sci 114 2417 2426
80. KanRSunXKolasNKAvdievichEKneitzB 2008 Comparative analysis of meiotic progression in female mice bearing mutations in genes of the DNA mismatch repair pathway. Biol Reprod 78 462 471
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 6
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Statistical Inference on the Mechanisms of Genome Evolution
- Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections
- Chromosomal Macrodomains and Associated Proteins: Implications for DNA Organization and Replication in Gram Negative Bacteria
- Maps of Open Chromatin Guide the Functional Follow-Up of Genome-Wide Association Signals: Application to Hematological Traits