{"id":7995,"date":"2022-08-13T14:40:35","date_gmt":"2022-08-13T11:40:35","guid":{"rendered":"https:\/\/www.ortaakarsu.net\/?p=7995"},"modified":"2022-08-13T14:40:38","modified_gmt":"2022-08-13T11:40:38","slug":"topoizomeraz-enzimleri-ve-islevleri","status":"publish","type":"post","link":"https:\/\/www.ortaakarsu.net\/?p=7995","title":{"rendered":"Topoizomeraz Enzimleri ve \u0130\u015flevleri"},"content":{"rendered":"\n<p class=\"wp-block-paragraph\"><strong>DNA s\u00fcper sarg\u0131s\u0131n\u0131n gev\u015femesi, topoizomeraz enzimlerinin \u00f6nemli bir i\u015flevidir. <\/strong>N\u00fckleer DNA olduk\u00e7a uzun bir polimerdir. Tek bir memeli genomu, yakla\u015f\u0131k 10-17 m3&#8217;l\u00fck bir h\u00fccre hacmine s\u0131k\u0131\u015ft\u0131r\u0131lan yakla\u015f\u0131k 2 metreye kar\u015f\u0131l\u0131k gelir. H\u00fccresel DNA, bu nedenle, \u00e7ok say\u0131da e\u011fri DNA alan\u0131 (d\u00f6ng\u00fcler) ve bu DNA alanlar\u0131 aras\u0131nda temas noktalar\u0131 olu\u015fturan y\u00fcksek oranda s\u0131k\u0131\u015ft\u0131r\u0131lmal\u0131d\u0131r. Ayr\u0131ca, <strong>DNA metabolizmas\u0131, transkripsiyon, replikasyon, rekombinasyon ve onar\u0131m i\u00e7in \u015fablon g\u00f6revi g\u00f6rmeleri i\u00e7in dubleksin iki zincirinin ayr\u0131lmas\u0131n\u0131 gerektirir.<\/strong> Replikasyon ve transkripsiyon komplekslerinin boyutu ve k\u00fctlesi nedeniyle, bu t\u00fcr komplekslerin DNA sarmal\u0131n\u0131n etraf\u0131nda serbest\u00e7e d\u00f6nmemeleri akla yatk\u0131nd\u0131r. Ek olarak, belirli bir replikasyon veya transkripsiyon kompleksini \u00e7evreleyen DNA b\u00f6lgesinin s\u0131n\u0131rl\u0131 serbest d\u00f6n\u00fc\u015f\u00fc nedeniyle, DNA metabolizmas\u0131 taraf\u0131ndan DNA s\u00fcper-sar\u0131lmas\u0131 \u00fcretilir. Bu nedenle, DNA, replikasyon veya transkripsiyon \u00e7atallar\u0131n\u0131n \u00fcst ak\u0131\u015f\u0131nda a\u015f\u0131r\u0131 sar\u0131lm\u0131\u015f (pozitif olarak s\u00fcper-sar\u0131lm\u0131\u015f) ve bu \u00e7atallar\u0131n ak\u0131\u015f a\u015fa\u011f\u0131s\u0131nda (negatif olarak s\u00fcper-sar\u0131lm\u0131\u015f) olma e\u011filimindedir. Ayr\u0131ca, n\u00fckleozom olu\u015fumu, DNA&#8217;y\u0131 histon oktamerinin etraf\u0131na sararak negatif a\u015f\u0131r\u0131 sarmay\u0131 k\u0131s\u0131tlar; bu, n\u00fckleozomun yan taraf\u0131nda pozitif s\u00fcper sarma olu\u015fturma e\u011filimi g\u00f6sterir. <strong>Bu t\u00fcr bir s\u00fcper-sar\u0131lma, DNA dupleksini s\u0131k\u0131la\u015ft\u0131r\u0131r ve topoizomerazlar taraf\u0131ndan gev\u015fetilmesi gerekir<\/strong>. <strong>Memeli topoizomeraz 1, topoizomeraz 1mt, topoizomeraz 2\u03b1 ve topoizomeraz 2\u03b2 hem pozitif hem de negatif a\u015f\u0131r\u0131 sarmay\u0131 gev\u015fetebilir<\/strong>. Bu nedenle, topoizomeraz enzimleri, s\u00fcper sarmall\u0131 kromatin b\u00f6lgelerinde (\u00f6zellikle transkripsiyon veya replikasyon kompleksleri ile birlikte) konsantre olma e\u011filimindedir.<\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full\"><img decoding=\"async\" width=\"565\" height=\"739\" src=\"https:\/\/www.ortaakarsu.net\/wp-content\/uploads\/topoizomeraz.png\" alt=\"Topoizomeraz enziminin g\u00f6revleri ve i\u015flevi\" class=\"wp-image-7996\" srcset=\"https:\/\/www.ortaakarsu.net\/wp-content\/uploads\/topoizomeraz-229x300.png 229w, https:\/\/www.ortaakarsu.net\/wp-content\/uploads\/topoizomeraz-500x654.png 500w, https:\/\/www.ortaakarsu.net\/wp-content\/uploads\/topoizomeraz-550x719.png 550w, https:\/\/www.ortaakarsu.net\/wp-content\/uploads\/topoizomeraz.png 565w\" sizes=\"(max-width: 565px) 100vw, 565px\" \/><figcaption>Topoizomeraz enziminin g\u00f6revleri ve i\u015flevi. G\u00f6rsel kayna\u011f\u0131na bakmak i\u00e7in <a href=\"https:\/\/doi.org\/10.1038\/nrc1977\">t\u0131klay\u0131n<\/a>.<\/figcaption><\/figure>\n<\/div>\n\n\n<p class=\"wp-block-paragraph\">DNA topoizomerazlar\u0131, b\u00f6l\u00fcnme ara ad\u0131m\u0131 (b\u00f6l\u00fcnme kompleksi olarak adland\u0131r\u0131l\u0131r) s\u0131ras\u0131nda <strong>topizomeraz I(TOP1) inhibit\u00f6rlerine<\/strong> kar\u015f\u0131 \u00f6zellikle hassast\u0131r. Genomdaki s\u0131kl\u0131klar\u0131na ra\u011fmen, TOP1 b\u00f6l\u00fcnme kompleksleri (TOP1ccs) normalde o kadar ge\u00e7icidir ki saptanamazlar, ancak kamptotesin ve farmas\u00f6tik t\u00fcrevleri taraf\u0131ndan spesifik ve geri d\u00f6n\u00fc\u015f\u00fcml\u00fc olarak yakalananlar bu komplekslerdir. Y\u00fcksek d\u00fczeyde h\u00fccresel TOP1cc&#8217;lerin DNA modifikasyonlar\u0131 veya apoptoz nedeniyle birikebilece\u011fini de belirtmek \u00f6nemlidir. TOP1ccs&#8217;nin yeniden ba\u011flanmas\u0131, serbest DNA ucu (<strong>5&#8242;-hidroksil ucu<\/strong>) taraf\u0131ndan tirozil-DNA-fosfodiester ba\u011f\u0131n\u0131n n\u00fckleofilik sald\u0131r\u0131s\u0131n\u0131 gerektirdi\u011finden, 5&#8242;-hidroksil-DNA ucunun m\u00fckemmel olmas\u0131 \u00e7ok \u00f6nemlidir ve kesilebilir tirozil-fosfodiester ba\u011f\u0131 ile hizalan\u0131r. Herhangi bir yanl\u0131\u015f hizalama, &#8220;dinlendirmeyi&#8221; yasaklar ve TOP1cc birikmesine yol a\u00e7ar. Bu nedenle, TOP1cc&#8217;ler, DNA&#8217;n\u0131n 5\u2032-hidroksil ucunun yanl\u0131\u015f hizalanmas\u0131 nedeniyle, <strong>DNA&#8217;n\u0131n 5\u2032-hidroksil ucunun yanl\u0131\u015f hizalanmas\u0131 nedeniyle baz uyumsuzluklar\u0131, baz oksidasyonu, bazik b\u00f6lgeler, kanserojen eklentiler ve \u00f6nceden var olan DNA k\u0131r\u0131lmalar\u0131n\u0131n b\u00f6lgelerinde birikir<\/strong>. Apoptotik TOP1cc&#8217;lerin olu\u015fumu, \u00e7e\u015fitli ko\u015fullarda ve staurosporin (her yerde bulunan bir apoptoz ind\u00fckleyici), arsenik trioksit, tubulin ve TOP2 inhibit\u00f6rleri ve FAS veya t\u00fcm\u00f6r nekroz fakt\u00f6r\u00fcn\u00fcn aktivasyonu dahil olmak \u00fczere \u00e7e\u015fitli apoptotik uyaranlara yan\u0131t olarak belgelenmi\u015ftir. \u0130lgili apoptozu ind\u00fckleyen ligand (TRAIL) (O. Sordet ve Y.P., yay\u0131nlanmam\u0131\u015f g\u00f6zlemler). Apoptotik TOP1cc&#8217;ler, apoptoz s\u0131ras\u0131nda g\u00f6zlenen erken biyokimyasal de\u011fi\u015fiklikler aras\u0131ndad\u0131r. En az\u0131ndan k\u0131smen, apoptoz s\u0131ras\u0131nda \u00fcretilen reaktif oksijen t\u00fcrleri taraf\u0131ndan \u00fcretilen oksidatif DNA modifikasyonlar\u0131ndan kaynaklan\u0131rlar. Kamptotesinler ve daha yeni topoizomeraz 1 inhibit\u00f6rleri Kamptotesin ilk olarak \u00c7in a\u011fac\u0131n\u0131n kabu\u011fundan, Camptotheca acuminata&#8217;den izole edildi. ABD Ulusal Kanser Enstit\u00fcs\u00fc (NCI) taraf\u0131ndan ve ayn\u0131 zamanda paklitaksel (Taxol) \u00fczerinde \u00e7al\u0131\u015fan ayn\u0131 gruplar taraf\u0131ndan ke\u015ffedilmi\u015f ve geli\u015ftirilmi\u015ftir. Kamptotesin karboksilat, 1970&#8217;lerin ortalar\u0131nda klinik olarak test edildi ve antikanser aktivitesi g\u00f6sterdi, ancak yan etkileri nedeniyle pazaran kald\u0131r\u0131ld\u0131. TOP1&#8217;in kamptotesinin h\u00fccresel hedefi oldu\u011fu ke\u015ffedildikten sonra, kamptotesinin suda \u00e7\u00f6z\u00fcn\u00fcr t\u00fcrevleri &#8211; topotekan ve irinotekan (CPT-11 olarak da bilinir) &#8211; ba\u015far\u0131yla geli\u015ftirildi.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">\u00c7evirinin yap\u0131ld\u0131\u011f\u0131 kaynak: Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond.\u00a0<em>Nat Rev Cancer<\/em>\u00a0<strong>6,\u00a0<\/strong>789\u2013802 (2006). DOI: <a href=\"https:\/\/doi.org\/10.1038\/nrc1977\">https:\/\/doi.org\/10.1038\/nrc1977<\/a><\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Topoizomeraz<\/strong> ve DNA hakk\u0131nda daha fazla bilgi i\u00e7in: <a href=\"https:\/\/www.ortaakarsu.net\/?p=6606\">Raltegravir \u2013 \u0130ntegraz \u0130nhibit\u00f6rlerinin \u0130lki<\/a>, <a href=\"https:\/\/www.ortaakarsu.net\/?p=7229\">Kemoterapi Yan Etkileri<\/a> adl\u0131 yaz\u0131lar\u0131 okuyabilirsiniz.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>DNA s\u00fcper sarg\u0131s\u0131n\u0131n gev\u015femesi, topoizomeraz enzimlerinin \u00f6nemli bir i\u015flevidir. N\u00fckleer  [&#8230;]<\/p>\n","protected":false},"author":1,"featured_media":7997,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[91],"tags":[110,323,104,92,125,143,106,9,322],"class_list":["post-7995","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-enzimler-biyokimya","tag-biyokimya","tag-dna","tag-enzim-inhibisyonu","tag-enzimler","tag-ilac","tag-ilac-gelistirme","tag-ilac-kesfi","tag-ilac-tasarimi","tag-topoizomeraz"],"acf":[],"_links":{"self":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts\/7995","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=7995"}],"version-history":[{"count":1,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts\/7995\/revisions"}],"predecessor-version":[{"id":7998,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/posts\/7995\/revisions\/7998"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=\/wp\/v2\/media\/7997"}],"wp:attachment":[{"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=7995"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=7995"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ortaakarsu.net\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=7995"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}