Hauv kev tshawb fawb tshiab, cov kws tshawb fawb los ntawm Weill Cornell Medical College hauv Tebchaws Meskas pom tias tus xa xov RNA (mRNA) muaj cov cim tshuaj tseem ceeb rau kev tiv thaiv kab mob tiv thaiv kab mob. Qhov kev tshawb pom no nthuav tawm 50 xyoo tsis paub txog lub hom phiaj ntawm cov kev hloov kho tshuaj lom neeg thiab qhia tias kev hloov kho mRNA yuam kev tuaj yeem ua rau qee yam kab mob autoimmune thiab inflammatory. Cov txiaj ntsig tau luam tawm online hauv Nature journal ntawm 1 Lub Ob Hlis 2023 nrog lub npe "mRNA aging shapes Cap2 methylome in mammalian mRNA".
Tshwj xeeb, lawv pom tias muaj kev hloov kho tshuaj lom neeg ntawm ib qhov chaw tshwj xeeb ntawm mRNA molecule- -methylation- - - muab kev tiv thaiv ntxiv rau mRNA, tiv thaiv nws los ntawm kev cuam tshuam ntawm cov tshuaj tiv thaiv kab mob.
Dr. Samie Jaffrey, tus kws sau ntawv sau thiab tus xibfwb ntawm Pharmacology ntawm Weill Cornell Medical College, tau hais tias, "Peb tau paub txij li xyoo 1970s tias kev hloov kho methyl rau qee qhov cuam tshuam rau kev ua haujlwm ntawm mRNA. Nws yog qhov zoo siab heev, yog li ntawd. , thaum kawg muaj xws li kev paub txog nws lub luag haujlwm. "
Lub mRNA yog theej los ntawm cov noob nquag, uas xa cov lus qhia tawm sab nraud ntawm DNA hauv lub nucleus mus rau qhov tseem ceeb ntawm lub cell, qhov chaw uas lawv tau muab txhais ua cov protein.
Jaffrey lab tau kawm txog cov txheej txheem siv los ntawm cov hlwb los tswj mRNA, piv txwv li, los txhawb lossis inhibit lawv cov kev txhais lus rau hauv cov protein. Ib qho ntawm cov txheej txheem tswj hwm no yog qhov sib ntxiv ntawm cov tshuaj hloov kho rau mRNA. Cov kev hloov kho tshuaj no feem ntau koom nrog kev hloov kho methyl. Hauv kev tshawb fawb yav dhau los, pab pawg Jaffrey tau tsim txoj hauv kev los kuaj xyuas ib qho ntawm cov kev hloov kho methyl, methyl-adenosine (m6A) - -, uas tswj mRNA stability hauv hlwb. Kev hloov hauv m6A tuaj yeem ua rau ntau hom mob qog noj ntshav.
Txawm li cas los xij, mRNA feem ntau muaj lwm qhov kev hloov kho tshuaj hu ua Cap 2. Hauv txoj kev tshawb fawb tshiab, Jaffrey thiab Vladimir Despic, thawj tus kws sau ntawv thiab tus kws tshawb fawb tom qab kawm tiav ntawm Jaffrey lab, tau kawm txog kev hloov kho tshuaj, nws txoj haujlwm tseem tsis tau paub.
Lub mRNA, ib yam li DNA uas tsim lawv los ntawm kev sau ntawv, yog txhua yam tsim los ntawm cov hlua ntawm cov hauv paus hu ua nucleotides. Thaum ib qho mRNA raug tsim, nws thawj nucleotide yog "npog (tseem hu ua capping)" los ntawm cov organic molecule me me. Thawj nucleotide kuj tau hloov kho los ntawm kev txuas ib pab pawg hu ua methyl pawg.
Thaum hom methylation no muaj nyob rau ntawm thawj nucleotide, mRNA paub tias muaj tus qauv "Cap 1" cap, uas paub tias pab tiv thaiv mRNA los ntawm lub cev tiv thaiv kab mob uas saib xyuas txhua yam zoo li tus kab mob RNA ntawm lub cell membrane.
Intrigingly, qee qhov mRNA tau txais cov tshuaj methylation ntxiv ntawm lawv cov nucleotide thib ob. Cov lus nug ntawm yog vim li cas qhov no ntxiv "Cap 2" methylation tshwm sim, thiab vim li cas nws tshwm sim ntawm qee qhov mRNA es tsis yog lwm tus, yuav luag tsis tuaj yeem teb - feem ntau vim tias cov kws kho tsiaj tsis muaj txoj hauv kev zoo los tshawb xyuas qhov twg mRNA muaj Cap 2 es tsis txhob Cap 1. .
Jaffrey thiab Despic pib lawv txoj kev tshawb fawb los ntawm kev tsim ib txoj kev zoo li no - - lawv hu li cas CLAM-Cap-seq- - - - -. Nrog rau txoj hauv kev no, lawv pom tias Cap 2 methylation tuaj yeem tshwm sim ntawm ib qho mRNA tab sis ntawm tus nqi qis, yog li nws nyiam pom tsuas yog ntawm cov mRNA uas tau muaj nyob hauv cytoplasm ntev.
Thaum kawg, lawv pom cov pov thawj tias thaum Cap 1 txo qis lub peev xwm ntawm mRNA los ua kom cov cellular antiviral mechanisms, Cap 2 muab kev tiv thaiv tseem ceeb ntxiv. Lawv tau pom tias thaum cellular mRNA tsuas yog Cap 1 hom, cov cellular mRNA qhib cov tshuaj tiv thaiv kab mob hauv cov hlwb, txawm tias tsis muaj tus kab mob.
Tab sis, cov neeg sau ntawv no pom tias Cap 2 ntau dhau kuj yog qhov phem. Thaum lawv cov hlwb tsim tau nrawm nrawm nrog Cap 2 rau hauv mRNA, lawv pom tias mRNA ntawm cov kab mob invading pib kis tau Cap 2, tiv thaiv lawv los ntawm kev tiv thaiv kab mob thiab tso cai rau cov kab mob no loj hlob tsis tswj. Jaffrey hais tias, "Peb xav tias Cap 2 methylation tshwm sim qeeb heev, tsis sai sai, kom txo tau txoj hauv kev uas nws thiaj li zais cov kab mob RNA sai sai los ntawm kev tshawb pom los ntawm lub cev tsis muaj zog."
Cov kev tshawb pom no, ntxiv rau kev daws qhov ntev-sawv Cap 2 puzzle, qhib cov lus qhia tshiab rau kev tshawb fawb kev txhais lus.Ib qho ua tau Dr Jaffrey tam sim no nrhiav yog qhov ua tsis taus ntawm Cap 1 / Cap 2 txheej txheem underlies qee cov kab mob autoimmune xws li lupus. thiab rheumatoid mob caj dab, thiab qhov kev kho rau qhov ua tsis taus no tuaj yeem yog kev kho tshiab rau cov kab mob no.
Lwm qhov ua tau, nws hais tias, yog txhawm rau txhawb kev tiv thaiv kab mob tiv thaiv kab mob los ntawm inhibiting Cap 2 thaum tsis muaj kab mob kis yam tsis muaj kev kho mob zoo dua.
Jaffrey tau hais tias, "Peb tseem tab tom kawm txog qhov ua tau ntawm kev siv Cap 2 hloov kho los ntawm kev txo cov teebmeem ntawm mRNA-raws li cov tshuaj kho mob (xws li cov tshuaj tiv thaiv) hauv hlwb.