LOCUS       NM_001330700            5814 bp    mRNA    linear   PRI 10-FEB-2025
DEFINITION  Homo sapiens DNA topoisomerase II beta (TOP2B), transcript variant
            1, mRNA.
ACCESSION   NM_001330700 XM_005265427
VERSION     NM_001330700.2
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 5814)
  AUTHORS   Bandak,A.F., Blower,T.R., Nitiss,K.C., Shah,V., Nitiss,J.L. and
            Berger,J.M.
  TITLE     Using energy to go downhill-a genoprotective role for ATPase
            activity in DNA topoisomerase II
  JOURNAL   Nucleic Acids Res 52 (3), 1313-1324 (2024)
   PUBMED   38038260
  REMARK    GeneRIF: Using energy to go downhill-a genoprotective role for
            ATPase activity in DNA topoisomerase II.
            Erratum:[Nucleic Acids Res. 2024 Feb 9;52(3):1525. doi:
            10.1093/nar/gkad1255.. PMID: 38153185]
REFERENCE   2  (bases 1 to 5814)
  AUTHORS   Mishra,S.V., Banerjee,A., Sarkar,D., Thangarathnam,V., Bagal,B.,
            Hasan,S.K. and Dutt,S.
  TITLE     DNA-PKcs-mediated transcriptional regulation of TOP2B drives
            chemoresistance in acute myeloid leukemia
  JOURNAL   J Cell Sci 137 (3) (2024)
   PUBMED   38240344
  REMARK    GeneRIF: DNA-PKcs-mediated transcriptional regulation of TOP2B
            drives chemoresistance in acute myeloid leukemia.
REFERENCE   3  (bases 1 to 5814)
  AUTHORS   Shu,J., Jiang,J., Wang,X., Yang,X., Zhao,G. and Cai,T.
  TITLE     MDM2 provides TOP2 poison resistance by promoting proteolysis of
            TOP2betacc in a p53-independent manner
  JOURNAL   Cell Death Dis 15 (1), 83 (2024)
   PUBMED   38263255
  REMARK    GeneRIF: MDM2 provides TOP2 poison resistance by promoting
            proteolysis of TOP2betacc in a p53-independent manner.
            Erratum:[Cell Death Dis. 2024 May 7;15(5):320. doi:
            10.1038/s41419-024-06634-5.. PMID: 38714647]
            Publication Status: Online-Only
REFERENCE   4  (bases 1 to 5814)
  AUTHORS   Cowell,I.G., Casement,J.W. and Austin,C.A.
  TITLE     To Break or Not to Break: The Role of TOP2B in Transcription
  JOURNAL   Int J Mol Sci 24 (19), 14806 (2023)
   PUBMED   37834253
  REMARK    GeneRIF: To Break or Not to Break: The Role of TOP2B in
            Transcription.
            Review article
            Publication Status: Online-Only
REFERENCE   5  (bases 1 to 5814)
  AUTHORS   Cepni,E., Borklu,E., Avci,S., Kalayci,T., Eraslan,S. and
            Kayserili,H.
  TITLE     Revisiting TOP2B-related phenotypes: Three new cases and literature
            review
  JOURNAL   Clin Genet 104 (2), 251-258 (2023)
   PUBMED   37068767
  REMARK    GeneRIF: Revisiting TOP2B-related phenotypes: Three new cases and
            literature review.
            Review article
REFERENCE   6  (bases 1 to 5814)
  AUTHORS   Zini,N., Santi,S., Ognibene,A., Bavelloni,A., Neri,L.M.,
            Valmori,A., Mariani,E., Negri,C., Astaldi-Ricotti,G.C. and
            Maraldi,N.M.
  TITLE     Discrete localization of different DNA topoisomerases in HeLa and
            K562 cell nuclei and subnuclear fractions
  JOURNAL   Exp Cell Res 210 (2), 336-348 (1994)
   PUBMED   8299728
REFERENCE   7  (bases 1 to 5814)
  AUTHORS   Jenkins,J.R., Ayton,P., Jones,T., Davies,S.L., Simmons,D.L.,
            Harris,A.L., Sheer,D. and Hickson,I.D.
  TITLE     Isolation of cDNA clones encoding the beta isozyme of human DNA
            topoisomerase II and localisation of the gene to chromosome 3p24
  JOURNAL   Nucleic Acids Res 20 (21), 5587-5592 (1992)
   PUBMED   1333583
REFERENCE   8  (bases 1 to 5814)
  AUTHORS   Tan,K.B., Dorman,T.E., Falls,K.M., Chung,T.D., Mirabelli,C.K.,
            Crooke,S.T. and Mao,J.
  TITLE     Topoisomerase II alpha and topoisomerase II beta genes:
            characterization and mapping to human chromosomes 17 and 3,
            respectively
  JOURNAL   Cancer Res 52 (1), 231-234 (1992)
   PUBMED   1309226
REFERENCE   9  (bases 1 to 5814)
  AUTHORS   Austin,C.A. and Fisher,L.M.
  TITLE     Isolation and characterization of a human cDNA clone encoding a
            novel DNA topoisomerase II homologue from HeLa cells
  JOURNAL   FEBS Lett 266 (1-2), 115-117 (1990)
   PUBMED   2163884
REFERENCE   10 (bases 1 to 5814)
  AUTHORS   Chung,T.D., Drake,F.H., Tan,K.B., Per,S.R., Crooke,S.T. and
            Mirabelli,C.K.
  TITLE     Characterization and immunological identification of cDNA clones
            encoding two human DNA topoisomerase II isozymes
  JOURNAL   Proc Natl Acad Sci U S A 86 (23), 9431-9435 (1989)
   PUBMED   2556712
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from AC093416.2.
            This sequence is a reference standard in the RefSeqGene project.
            
            On Apr 28, 2020 this sequence version replaced NM_001330700.1.
            
            Summary: This gene encodes a DNA topoisomerase, an enzyme that
            controls and alters the topologic states of DNA during
            transcription. This nuclear enzyme is involved in processes such as
            chromosome condensation, chromatid separation, and the relief of
            torsional stress that occurs during DNA transcription and
            replication. It catalyzes the transient breaking and rejoining of
            two strands of duplex DNA which allows the strands to pass through
            one another, thus altering the topology of DNA. Two forms of this
            enzyme exist as likely products of a gene duplication event. The
            gene encoding this form, beta, is localized to chromosome 3 and the
            alpha form is localized to chromosome 17. The gene encoding this
            enzyme functions as the target for several anticancer agents and a
            variety of mutations in this gene have been associated with the
            development of drug resistance. Reduced activity of this enzyme may
            also play a role in ataxia-telangiectasia. Alternative splicing
            results in multiple transcript variants. [provided by RefSeq, Aug
            2016].
            
            Transcript Variant: This variant (1) represents the longer
            transcript and encodes the longer isoform (1).
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: SRR14038191.438641.1,
                                           SRR14038194.3957084.1 [ECO:0000332]
            RNAseq introns              :: mixed sample support SAMEA1965299,
                                           SAMEA1966682 [ECO:0006172]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match     :: ENST00000264331.9/ ENSP00000264331.4
            RefSeq Select criteria :: based on manual assertion, conservation,
                                      longest protein
            ##RefSeq-Attributes-END##
            COMPLETENESS: complete on the 3' end.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-679               AC093416.2         164040-164718       c
            680-850             AC093416.2         145111-145281       c
            851-941             AC093416.2         143505-143595       c
            942-1005            AC093416.2         142133-142196       c
            1006-1151           AC093416.2         137976-138121       c
            1152-1249           AC093416.2         137026-137123       c
            1250-1462           AC093416.2         135747-135959       c
            1463-1636           AC093416.2         133652-133825       c
            1637-1738           AC093416.2         132504-132605       c
            1739-1876           AC093416.2         132257-132394       c
            1877-2015           AC093416.2         130612-130750       c
            2016-2173           AC093416.2         130123-130280       c
            2174-2299           AC093416.2         129840-129965       c
            2300-2410           AC093416.2         128846-128956       c
            2411-2516           AC093416.2         128658-128763       c
            2517-2626           AC093416.2         126998-127107       c
            2627-2719           AC093416.2         126583-126675       c
            2720-2834           AC093416.2         126371-126485       c
            2835-2956           AC093416.2         124493-124614       c
            2957-3105           AC093416.2         124108-124256       c
            3106-3337           AC093416.2         123326-123557       c
            3338-3472           AC093416.2         120493-120627       c
            3473-3673           AC093416.2         119673-119873       c
            3674-3869           AC093416.2         118465-118660       c
            3870-3961           AC093416.2         118229-118320       c
            3962-4117           AC093416.2         115242-115397       c
            4118-4201           AC093416.2         115016-115099       c
            4202-4396           AC093416.2         112326-112520       c
            4397-4541           AC093416.2         109379-109523       c
            4542-4703           AC093416.2         108994-109155       c
            4704-4908           AC093416.2         106982-107186       c
            4909-4988           AC093416.2         105854-105933       c
            4989-5099           AC093416.2         104571-104681       c
            5100-5225           AC093416.2         100911-101036       c
            5226-5320           AC093416.2         99246-99340         c
            5321-5814           AC093416.2         97795-98288         c
FEATURES             Location/Qualifiers
     source          1..5814
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="3"
                     /map="3p24.2"
     gene            1..5814
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /note="DNA topoisomerase II beta"
                     /db_xref="GeneID:7155"
                     /db_xref="HGNC:HGNC:11990"
                     /db_xref="MIM:126431"
     exon            1..679
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     CDS             611..5491
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /EC_number="5.6.2.2"
                     /note="isoform 1 is encoded by transcript variant 1; DNA
                     topoisomerase 2-beta; topo II beta; DNA topoisomerase II,
                     180 kD; topoisomerase II beta; antigen MLAA-44; U937
                     associated antigen; topoisomerase IIb; DNA topoisomerase
                     II, beta isozyme; topoisomerase (DNA) II beta 180kDa"
                     /codon_start=1
                     /product="DNA topoisomerase 2-beta isoform 1"
                     /protein_id="NP_001317629.1"
                     /db_xref="CCDS:CCDS82746.1"
                     /db_xref="GeneID:7155"
                     /db_xref="HGNC:HGNC:11990"
                     /db_xref="MIM:126431"
                     /translation="MAKSGGCGAGAGVGGGNGALTWVTLFDQNNAAKKEESETANKND
                     SSKKLSVERVYQKKTQLEHILLRPDTYIGSVEPLTQFMWVYDEDVGMNCREVTFVPGL
                     YKIFDEILVNAADNKQRDKNMTCIKVSIDPESNIISIWNNGKGIPVVEHKVEKVYVPA
                     LIFGQLLTSSNYDDDEKKVTGGRNGYGAKLCNIFSTKFTVETACKEYKHSFKQTWMNN
                     MMKTSEAKIKHFDGEDYTCITFQPDLSKFKMEKLDKDIVALMTRRAYDLAGSCRGVKV
                     MFNGKKLPVNGFRSYVDLYVKDKLDETGVALKVIHELANERWDVCLTLSEKGFQQISF
                     VNSIATTKGGRHVDYVVDQVVGKLIEVVKKKNKAGVSVKPFQVKNHIWVFINCLIENP
                     TFDSQTKENMTLQPKSFGSKCQLSEKFFKAASNCGIVESILNWVKFKAQTQLNKKCSS
                     VKYSKIKGIPKLDDANDAGGKHSLECTLILTEGDSAKSLAVSGLGVIGRDRYGVFPLR
                     GKILNVREASHKQIMENAEINNIIKIVGLQYKKSYDDAESLKTLRYGKIMIMTDQDQD
                     GSHIKGLLINFIHHNWPSLLKHGFLEEFITPIVKASKNKQELSFYSIPEFDEWKKHIE
                     NQKAWKIKYYKGLGTSTAKEAKEYFADMERHRILFRYAGPEDDAAITLAFSKKKIDDR
                     KEWLTNFMEDRRQRRLHGLPEQFLYGTATKHLTYNDFINKELILFSNSDNERSIPSLV
                     DGFKPGQRKVLFTCFKRNDKREVKVAQLAGSVAEMSAYHHGEQALMMTIVNLAQNFVG
                     SNNINLLQPIGQFGTRLHGGKDAASPRYIFTMLSTLARLLFPAVDDNLLKFLYDDNQR
                     VEPEWYIPIIPMVLINGAEGIGTGWACKLPNYDAREIVNNVRRMLDGLDPHPMLPNYK
                     NFKGTIQELGQNQYAVSGEIFVVDRNTVEITELPVRTWTQVYKEQVLEPMLNGTDKTP
                     ALISDYKEYHTDTTVKFVVKMTEEKLAQAEAAGLHKVFKLQTTLTCNSMVLFDHMGCL
                     KKYETVQDILKEFFDLRLSYYGLRKEWLVGMLGAESTKLNNQARFILEKIQGKITIEN
                     RSKKDLIQMLVQRGYESDPVKAWKEAQEKAAEEDETQNQHDDSSSDSGTPSGPDFNYI
                     LNMSLWSLTKEKVEELIKQRDAKGREVNDLKRKSPSDLWKEDLAAFVEELDKVESQER
                     EDVLAGMSGKAIKGKVGKPKVKKLQLEETMPSPYGRRIIPEITAMKADASKKLLKKKK
                     GDLDTAAVKVEFDEEFSGAPVEGAGEEALTPSVPINKGPKPKREKKEPGTRVRKTPTS
                     SGKPSAKKVKKRNPWSDDESKSESDLEETEPVVIPRDSLLRRAAAERPKYTFDFSEEE
                     DDDADDDDDDNNDLEELKVKASPITNDGEDEFVPSDGLDKDEYTFSPGKSKATPEKSL
                     HDKKSQDFGNLFSFPSYSQKSEDDSAKFDSNEEDSASVFSPSFGLKQTDKVPSKTVAA
                     KKGKPSSDTVPKPKRAPKQKKVVEAVNSDSDSEFGIPKKTTTPKGKGRGAKKRKASGS
                     ENEGDYNPGRKTSKTTSKKPKKTSFDQDSDVDIFPSDFPTEPPSLPRTGRARKEVKYF
                     AESDEEEDDVDFAMFN"
     exon            680..850
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            851..941
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            942..1005
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            1006..1151
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            1152..1249
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            1250..1462
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            1463..1636
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            1637..1738
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            1739..1876
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            1877..2015
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2016..2173
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2174..2299
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2300..2410
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2411..2516
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2517..2626
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2627..2719
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2720..2834
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2835..2956
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            2957..3105
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            3106..3337
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            3338..3472
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            3473..3673
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            3674..3869
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            3870..3961
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            3962..4117
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            4118..4201
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            4202..4396
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            4397..4541
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            4542..4703
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            4704..4908
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            4909..4988
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            4989..5099
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            5100..5225
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            5226..5320
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     exon            5321..5814
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /inference="alignment:Splign:2.1.0"
     regulatory      5797..5802
                     /regulatory_class="polyA_signal_sequence"
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /note="hexamer: ATTAAA"
     polyA_site      5814
                     /gene="TOP2B"
                     /gene_synonym="BILU; top2beta; TOPIIB"
                     /note="major polyA site"
ORIGIN      
        1 gtgtgtgcgg tgttatgccg gacaagaggg aggtgaccgt ggcggcggcg gcggcggctc
       61 tgtttattgt ccctctcggt gtgtgtgtgt gaggaaatcg gggctgcagc gaggctaagg
      121 ctgcctttga agcagcggcg gcgaccggga cgactactct ggcgactcga gtggctggcc
      181 ttcgcggagt gtgagaagga caaggcacct ctgcgtcctc gccacgtccg agcgcctcgg
      241 gctccccggc cgccctcgcg gctcgcacgc ccgggcttca gcccggcctg cagcggcgcc
      301 cgcgggcggg cgagaaggca acgccgccgc tcggccgccg ccggtcgctc cctgctttct
      361 cctcagccgc cgcgctaggc ccgggcgacg cggacgccgc gcctcgagtt tgagggcagc
      421 cggcggcgcg gcctcctcag cgggctcggc tggacgtccg ctccggatct tcgcgatggg
      481 gcgcgggggt cggcgcggct aggagtgcgg cgagtggagc ggtgggtgcg gagcggcggg
      541 gcccagcggc ccgcagggag gcgggagcgg cggctgcggc ctcagggcct gtgagctgga
      601 ggcactcgcc atggccaagt cgggtggctg cggcgcggga gccggcgtgg gcggcggcaa
      661 cggggcactg acctgggtga ctctttttga tcagaacaat gctgcaaaaa aagaagagtc
      721 agaaactgcc aacaaaaatg attcttcaaa gaagttgtct gttgagagag tgtatcagaa
      781 gaagacacaa cttgaacaca ttcttcttcg tcctgataca tatattgggt cagtggagcc
      841 attgacgcag ttcatgtggg tgtatgatga agatgtagga atgaattgca gggaggttac
      901 ctttgtgcca ggtttataca agatctttga tgaaattttg gttaatgctg ctgacaataa
      961 acagagggat aagaacatga cttgtattaa agtttctatt gatcctgaat ctaacattat
     1021 aagcatttgg aataatggga aaggcattcc agtagtagaa cacaaggtag agaaagttta
     1081 tgttcctgct ttaatttttg gacagctttt aacatccagt aactatgatg atgatgagaa
     1141 aaaagttaca ggtggtcgta atggttatgg tgcaaaactt tgtaatattt tcagtacaaa
     1201 gtttacagta gaaacagctt gcaaagaata caaacacagt tttaagcaga catggatgaa
     1261 taatatgatg aagacttctg aagccaaaat taaacatttt gatggtgaag attacacatg
     1321 cataacattc caaccagatc tgtccaaatt taagatggaa aaacttgaca aggatattgt
     1381 ggccctcatg actagaaggg catatgattt ggctggttcg tgtagagggg tcaaggtcat
     1441 gtttaatgga aagaaattgc ctgtaaatgg atttcgcagt tatgtagatc tttatgtgaa
     1501 agacaaattg gatgaaactg gggtggccct gaaagttatt catgagcttg caaatgaaag
     1561 atgggatgtt tgtctcacat tgagtgaaaa aggattccag caaatcagct ttgtaaatag
     1621 tattgcaact acaaaaggtg gacggcacgt ggattatgtg gtagatcaag ttgttggtaa
     1681 actgattgaa gtagttaaga aaaagaacaa agctggtgta tcagtgaaac catttcaagt
     1741 aaaaaaccat atatgggttt ttattaattg ccttattgaa aatccaactt ttgattctca
     1801 gactaaggaa aacatgactc tgcagcccaa aagttttggg tctaaatgcc agctgtcaga
     1861 aaaatttttt aaagcagcct ctaattgtgg cattgtagaa agtatcctga actgggtgaa
     1921 atttaaggct cagactcagc tgaataagaa gtgttcatca gtaaaataca gtaaaatcaa
     1981 aggtattccc aaactggatg atgctaatga tgctggtggt aaacattccc tggagtgtac
     2041 actgatatta acagagggag actctgccaa atcactggct gtgtctggat taggtgtgat
     2101 tggacgagac agatacggag tttttccact caggggcaaa attcttaatg tacgggaagc
     2161 ttctcataaa cagatcatgg aaaatgctga aataaataat attattaaaa tagttggtct
     2221 acaatataag aaaagttacg atgatgcaga atctctgaaa accttacgct atggaaagat
     2281 tatgattatg accgatcagg atcaagatgg ttctcacata aaaggcctgc ttattaattt
     2341 catccatcac aattggccat cacttttgaa gcatggtttt cttgaagagt tcattactcc
     2401 tattgtaaag gcaagcaaaa ataagcagga actttccttc tacagtattc ctgaatttga
     2461 cgaatggaaa aaacatatag aaaaccagaa agcctggaaa ataaagtact ataaaggatt
     2521 gggtactagt acagctaaag aagcaaagga atattttgct gatatggaaa ggcatcgcat
     2581 cttgtttaga tatgctggtc ctgaagatga tgctgccatt accttggcat ttagtaagaa
     2641 gaagattgat gacagaaaag aatggttaac aaattttatg gaagaccgga gacagcgtag
     2701 gctacatggc ttaccagagc aatttttata tggtactgca acaaagcatt tgacttataa
     2761 tgatttcatc aacaaggaat tgattctctt ctcaaactca gacaatgaaa gatctatacc
     2821 atctcttgtt gatggcttta aacctggcca gcggaaagtt ttatttacct gtttcaagag
     2881 gaatgataaa cgtgaagtaa aagttgccca gttggctggc tctgttgctg agatgtcggc
     2941 ttatcatcat ggagaacaag cattgatgat gactattgtg aatttggctc agaactttgt
     3001 gggaagtaac aacattaact tgcttcagcc tattggtcag tttggaactc ggcttcatgg
     3061 tggcaaagat gctgcaagcc ctcgttatat tttcacaatg ttaagcactt tagcaaggct
     3121 actttttcct gctgtggatg acaacctcct taagttcctt tatgatgata atcaacgtgt
     3181 agagcctgag tggtatattc ctataattcc catggtttta ataaatggtg ctgagggcat
     3241 tggtactgga tgggcttgta aactacccaa ctatgatgct agggaaattg tgaacaatgt
     3301 cagacgaatg ctagatggcc tggatcctca tcccatgctt ccaaactaca aaaactttaa
     3361 aggcacgatt caagaacttg gtcaaaacca gtatgcagtc agtggtgaaa tatttgtagt
     3421 ggacagaaac acagtagaaa ttacagagct tccagttaga acttggacac aggtatataa
     3481 agaacaggtt ttagaaccta tgctaaatgg aacagataaa acaccagcat taatttctga
     3541 ttataaagaa tatcatactg acacaactgt gaaatttgtg gtgaaaatga ctgaagagaa
     3601 actagcacaa gcagaagctg ctggactgca taaagttttt aaacttcaaa ctactcttac
     3661 ttgtaattcc atggtacttt ttgatcatat gggatgtctg aagaaatatg aaactgtgca
     3721 agacattctg aaagaattct ttgatttacg attaagttat tacggtttac gtaaggagtg
     3781 gcttgtggga atgttgggag cagaatctac aaagcttaac aatcaagccc gtttcatttt
     3841 agagaagata caagggaaaa ttactataga gaataggtca aagaaagatt tgattcaaat
     3901 gttagtccag agaggttatg aatctgaccc agtgaaagcc tggaaagaag cacaagaaaa
     3961 ggcagcagaa gaggatgaaa cacaaaacca gcatgatgat agttcctccg attcaggaac
     4021 tccttcaggc ccagatttta attatatttt aaatatgtct ctgtggtctc ttactaaaga
     4081 aaaagttgaa gaactgatta aacagagaga tgcaaaaggg cgagaggtca atgatcttaa
     4141 aagaaaatct ccttcagatc tttggaaaga ggatttagcg gcatttgttg aagaactgga
     4201 taaagtggaa tctcaagaac gagaagatgt tctggctgga atgtctggaa aagcaattaa
     4261 aggtaaagtt ggcaaaccta aggtgaagaa actccagttg gaagagacaa tgccctcacc
     4321 ttatggcaga agaataattc ctgaaattac agctatgaag gcagatgcca gcaaaaagtt
     4381 gctgaagaag aagaagggtg atcttgatac tgcagcagta aaagtggaat ttgatgaaga
     4441 attcagtgga gcaccagtag aaggtgcagg agaagaggca ttgactccat cagttcctat
     4501 aaataaaggt cccaaaccta agagggagaa gaaggagcct ggtaccagag tgagaaaaac
     4561 acctacatca tctggtaaac ctagtgcaaa gaaagtgaag aaacggaatc cttggtcaga
     4621 tgatgaatcc aagtcagaaa gtgatttgga agaaacagaa cctgtggtta ttccaagaga
     4681 ttctttgctt aggagagcag cagccgaaag acctaaatac acatttgatt tctcagaaga
     4741 agaggatgat gatgctgatg atgatgatga tgacaataat gatttagagg aattgaaagt
     4801 taaagcatct cccataacaa atgatgggga agatgaattt gttccttcag atgggttaga
     4861 taaagatgaa tatacatttt caccaggcaa atcaaaagcc actccagaaa aatctttgca
     4921 tgacaaaaaa agtcaggatt ttggaaatct cttctcattt ccttcatatt ctcagaagtc
     4981 agaagatgat tcagctaaat ttgacagtaa tgaagaagat tctgcttctg ttttttcacc
     5041 atcatttggt ctgaaacaga cagataaagt tccaagtaaa acggtagctg ctaaaaaggg
     5101 aaaaccgtct tcagatacag tccctaagcc caagagagcc ccaaaacaga agaaagtagt
     5161 agaggctgta aactctgact cggattcaga atttggcatt ccaaagaaga ctacaacacc
     5221 aaaaggtaaa ggccgagggg caaagaaaag gaaagcatct ggctctgaaa atgaaggcga
     5281 ttataaccct ggcaggaaaa catccaaaac aacaagcaag aaaccgaaga agacatcttt
     5341 tgatcaggat tcagatgtgg acatcttccc ctcagacttc cctactgagc caccttctct
     5401 gccacgaacc ggtcgggcta ggaaagaagt aaaatatttt gcagagtctg atgaagaaga
     5461 agatgatgtt gattttgcaa tgtttaatta agtgcccaaa gagcacaaac atttttcaac
     5521 aaatatcttg tgttgtcctt ttgtcttctc tgtctcagac ttttgtacat ctggcttatt
     5581 ttaatgtgat gatgtaattg acggtttttt attattgtgg taggcctttt aacattttgt
     5641 tcttacacat acagttttat gctctttttt actcattgaa atgtcacgta ctgtctgatt
     5701 ggcttgtaga attgttatag actgccgtgc attagcacag attttaattg tcatggttac
     5761 aaactacaga cctgcttttt gaaatgaaat ttaaacatta aaaatggaac tgtg
//
