Haɗin kanjamau
 Haɗin kanjamau | |
|---|---|
| Bayanai | |
| Fuskar | Kanjamau |
Cutar AIDS ("ciwon rashin rigakafi") ta haifar da kwayar cutar ta mutum (HIV). Mutanen da ke fama da Cutar kanjamau suna da abin da ake kira "ciwon cutar kanjamain HIV". Lokacin da kwayar cutar ta kamu da cutar, ɓarkewar farji, ko jini sun haɗu da Membrane na mucous ko fata da ta karye na mutumin da ba a kamu da cutar ba, ana iya canja kwayar cutar HIV zuwa ga mutumin da ba shi da cutar ("canjin kwance"), wanda ke haifar da wani kamuwa. Bugu da ƙari, ana iya ba da kwayar cutar kanjamau daga mata masu juna biyu da suka kamu da cutar zuwa jaririnsu marar kamuwa da cutar a lokacin daukar ciki da / ko haihuwa ("rarrabawar tsaye"), ko ta hanyar shayarwa. A sakamakon kamuwa da kwayar cutar kanjamau, wani ɓangare na waɗannan mutane za su ci gaba kuma su ci gaba da kamuwa da cutar kanjamauyyar cuta.
HIV retrovirus ne, wanda ya ƙunshi babban iyali daban-daban na ƙwayoyin RNA waɗanda ke yin kwafin DNA na kwayar halitta RNA bayan kamuwa da kwayar halitta. Wani muhimmin mataki a cikin sake zagayowar kwayar cutar HIV-1 da sauran retroviruses shine hadewar wannan DNA mai kwayar cuta a cikin DNA mai karɓar bakuncin. Ana yin kwayar halittar RNA na zuriyar virions da samfuri don fassarar sunadarai na kwayar cuta lokacin da aka rubuta DNA na kwayar cutar.
Bayani na baya: HIV-1 Integrase
[gyara sashe | gyara masomin]
Haɗin DNA na HIV a cikin DNA ɗin mai masaukin shine muhimmin mataki a cikin tsarin rayuwar HIV. Fahimtar tsarin haɗin kai zai samar da tsari don samun fahimtar wurare da yawa masu yuwuwar yin maganin cutar HIV da AIDS. Enzyme na HIV don shigar da nau'in DNA na kwayar halittarsa a cikin kwayar halittar DNA ana kiransa "haɗin kai". Haɗin HIV-1 yana haɓaka aikin "yanke-da-manna" na yanke DNA mai gida da haɗa kwayoyin halittar lardi zuwa ƙarshen da aka yanke. Wannan furotin, wanda tsawon amino acid 288, ya ƙunshi “yankuna” guda uku, a cikin wannan tsari:
1. Amino (N) -terminal domain: Wani lokaci ana kiransa "zinc finger", Ya N-terminal ya ƙunshi HHCC mai kiyayewa, His, da Cys residues, wani dalili wanda ke aiki don ɗaure zinc. Ayyukan yankin N-terminal ba a bayyane yake ba, amma ana zaton yana taimakawa integrase wajen samar da multimers (ƙungiyoyin ƙwayoyin integrase da yawa).
2. Yankin tsakiya na tsakiya (ko "ƙananan ƙwayoyin"): Babban ƙwayoyin ƙwayoyin cuta ya ƙunshi DDE catalytic triad na amino acid, ko ragowar acid, wanda ke sarrafa ɗaurewa tare da ƙarfe mai ƙwayoyin (yawanci Mg2 + ko Mn2−), yana samar da shafin catalytic mai aiki. Game da HIV-1 integrase, raguwar sune Asp64, Asp116, da Glu152. Wannan yanki kuma an kiyaye shi sosai a lokacin juyin halitta.
Yankin kwayar cutar HIV-1 yana bayyana dimeric a cikin bayani kuma a cikin sifofin crystal. Faɗin sararin samaniya na mahaɗar dimer yana nuna cewa yana da mahimmanci a ilimin halitta. Shafukan sakawa akan kowane madaidaicin DNA ɗin da aka yi niyya an raba su da nau'i-nau'i na tushe guda 5, waɗanda ke daidai da kusan 15 Å don nau'in DNA na helical B, yana nuna cewa yankin catalytic (ko sashin aikin) na haɗawa ya kamata ya ƙunshi rukunin shafuka biyu masu aiki da aka rabu ta hanyar tazara. Wannan ya ce, tazarar da ke tsakanin wuraren aiki a cikin kusan , da kuma girman girman girman 30 Å. Ƙarƙashin tsammanin cewa an adana ƙirar dimer a cikin multimer mai aiki, aƙalla tetramer na haɗawa dole ne a buƙaci cikakken haɗin kai don ci gaba.
3. Yankin Carboxy (C) - yankin ƙarshe: Yankin C-terminal ba takamaiman ba ne ke ɗaure DNA. Tunda shafukan haɗin kai a cikin DNA da aka yi niyya ba su da takamaiman, ana tunanin cewa wannan yanki na iya aiki tare a wasu hanyoyi tare da DNA da aka nufa. Bayanan da aka samo daga gwaje-gwaje tare da chimeric integrases sun nuna cewa ganewar shafin da aka yi niyya ana sarrafa shi ta hanyar babban yankin. Nazarin haɗin giciye ya kuma nuna cewa yankin C-terminal yana aiki tare da yankin subterminal kawai a cikin iyakar DNA na kwayar cuta.
A lokacin tsarin hadewa, enzyme na HIV integrase yana yin mahimman halayen halayen haɗi guda biyu. Na farko shine sarrafawa na 3 na DNA na HIV, sannan kuma canja wurin DNA na HIV zuwa cikin DNA mai karɓar bakuncin. Haɗin DNA na HIV na iya faruwa ko dai a cikin rarraba ko hutawa sel, kuma enzyme na HIV integrase na iya kasancewa a cikin nau'in monomer, dimer, tetramer, kuma mai yiwuwa ma da siffofin mafi girma (kamar octomers). Kowane kwayar cutar kanjamau yana da kimanin 40 zuwa 100 na integrase enzyme.
Ayyukan Integrase na musamman ne ga retroviruses; ba a buƙatar ƙwayoyin ɗan adam don yankewa da shafawa na DNA a cikin kwayar halitta. Saboda wannan dalili, masu hana integrase sune manyan manufofi don haɓaka maganin magani don kamuwa da cutar kanjamau da cutar kansar AIDS, tunda hana integrase bai kamata ya hana ayyukan yau da kullun a cikin sel na mutum ba.
Hanyar Haɗin kanjamau
[gyara sashe | gyara masomin]
Haɗin kanjamau shine saka kwayar cutar kanjamau a cikin kwayar halitta ta kwayar cutar.[1] Tsarin hadewar kwayar cutar kanjamau ya ƙunshi matakai shida na jerin:
Haɗuwa da HIV Integrase zuwa DNA na HIV
[gyara sashe | gyara masomin]Mataki na farko na tsarin haɗin kai yana faruwa a cikin cytoplasm na tantanin halitta bayan kammala jujjuyawar kwayar cutar HIV zuwa c-DNA. Wannan matakin ya ƙunshi ɗaure haɗakarwa - mai yiwuwa a cikin nau'in dimer - zuwa kowane ƙarshen sabuwar kwayar cutar HIV c-DNA. Daurin yana faruwa a takamaiman jeri a cikin yankuna masu maimaitawa mai tsayi. Rukunin DNA na hade-hade-HIV wani bangare ne na kwayar halittar nucleoprotein intracellular da aka sani da " hadaddun hada-hada" (PIC). Wannan hadaddun ya ƙunshi DNA na HIV na layi, sunadaran ƙwayoyin cuta, da kuma sunadaran da ke karbar bakuncin. Sunadaran ƙwayoyin cuta sun haɗa da haɗakarwa, nucleocapsid, matrix, furotin mai hoto hoto (Vpr), da jujjuya bayanan rubutu. Haka kuma wasu sunadaran sunadaran za su iya zama wani ɓangare na wannan hadaddun, ko da yake ba a sani ba ko wasu ko duk sun shiga cikin hadadden tsarin kafin jigilar makaman nukiliya.
A cikin mataki na biyu na tsarin haɗin kai, wanda kuma ke faruwa a cikin cytoplasm mai watsa shiri, haɗin haɗin gwiwar ya raba DNA na hoto a kowane 3 'karshen. Wannan matakin ɓarkewar yana cire GT dinucleotides akan 3'-gefe na yankin CA dinucleotide da aka kiyaye. Ragewar dinucleotide a kowane viral DNA 3'-karshen yana haifar da dinucleotide 5' "overhang" da tsaka-tsaki mai amsawa wanda ya ƙunshi ƙungiyar 3'-hydroxyl. Wannan mataki na aiki na 3' shine farkon maɓalli biyu masu mahimmancin halayen haɓakawa ta hanyar haɗakarwar enzyme, kuma yana shirya DNA na hoto don haɗawa cikin DNA mai gida. A madadin ra'ayi na ɗaurin DNA da 3'-aiki na sarrafawa, nau'in tetramer na haɗawa (ba dimer ba) yana ɗaure zuwa ƙarshen DNA na HIV, sa'an nan kuma ya raba 3' iyakar.
Translocation na HIV integrase zuwa kwayar halitta (Nuclear Translocation)
[gyara sashe | gyara masomin]A mataki na uku na tsarin hadewa, ana jigilar hadaddun preintegration zuwa cikin tsakiya na tantanin halitta, yana shiga ta hanyar daya daga cikin hadaddun nukiliya.
Haɗuwa da hadaddun preintegration zuwa ga mai karɓar bakuncin DNA
[gyara sashe | gyara masomin]A cikin tsakiya, ruwan tabarau na furotin mai masaukin epithelium-wanda aka samu girma factor/p75, wanda aka fi sani da shi a takaice kamar LEDGF/p75, yana ɗaure ga hadaddun haɗakarwa da DNA mai watsa shiri. LEDGF/p75 yana aiki azaman furotin mai haɗawa (ko gada) tsakanin hadaddun haɗawa da DNA mai masaukin baki. Jerin daurin LEDGF/p75, DNA mai masaukin baki, da hadadden hada-hada ya kasance babu tabbas. A cikin sigar ɗaya, LEDGF/p75 yana ɗaure farko zuwa hadaddun haɗin kai sannan kuma ga DNA mai masaukin baki. A gefe guda, LEDGF/p75 na iya ɗaure farko zuwa DNA mai watsa shiri sannan zuwa hadaddun haɗaɗɗiyar. Ba tare da la'akari da jerin ba, an yi imanin cewa kasancewar LEDGF/p75 yana haifar da haɓakar dimers da ke gabatowa da juna don samar da tetramer.
Canja wurin DNA na HIV a cikin mai karɓar bakuncin DNA (Sanyawar Strand)
[gyara sashe | gyara masomin]Mataki na gaba, yanayin canja wurin igiya, yana faruwa a cikin mahaifar tantanin halitta kuma ya ƙunshi muhimmin mataki na shigar da kwayar cutar HIV cikin wani yanki da aka zaɓa na DNA ɗin mai masaukin baki. Yankin shigarwa ya ƙunshi jerin palindromic mara ƙarfi da aka adana. An ƙaddamar da wannan matakin canja wuri yayin da haɗin kan HIV ke haifar da harin ƙungiyar HIV DNA 3'-hydroxyl akan DNA mai gida. Harin DNA na HIV yana faruwa ne akan saɓo daban-daban na DNA ɗin mai masaukin baki a cikin tsari mai ban sha'awa, yawanci 4-6 tushe guda biyu baya. Wannan halayen yana haifar da rabuwa na shaidu a cikin nau'i-nau'i na DNA na rundunar da ke tsakanin raguwa, da haɗuwa da ƙungiyoyin HIV 3'-hydroxyl tare da mai watsa shiri DNA 5' phosphate ƙare. A wannan lokacin, sabon yankin DNA mai ɗaukar hoto ya bayyana.
Gyara gibin da aka kafa a cikin tsarin canja wurin igiya ("Gap Repair")
[gyara sashe | gyara masomin]
Bayan tsarin canja wuri, kwayar cutar HIV-DNA da mahaɗar DNA ɗin suna da yankuna na DNA da ba a haɗa su ba, wanda ake kira DNA “gaps”. Bugu da kari, nau'i biyu na tushe biyu na yankin 5 na 'yankin' 'na Birnin Vi da sauri DNA ta ci gaba da hanzari bayan canja wuri. Shigar da sabon DNA na HIV da sauran gibin da ke gefen rukunin yanar gizon a halin yanzu ana tunanin haifar da amsawar lalacewar DNA ta wayar salula, amma yawancin wannan tsarin ya kasance mai hasashe. Ana tsammanin amsawar lalacewar DNA mai masaukin yana da mahimmanci a mataki na ƙarshe na haɗin kai, wanda aka sani da "gyaran rata" kuma yana iya buƙatar akalla enzymes mai watsa shiri guda uku - polymerase, nuclease, da ligase. A cikin mataki na farko na gyaran rata, ana tunanin cewa polymerase enzyme (s) ya shimfiɗa (s) DNA mai watsa shiri a kowane ƙarshen kuma, ta haka, cika gibin. Na gaba, yana yiwuwa aikin rundunonin ƙwayoyin cuta ya cire 5' dinucleotide "flaps" akan DNA na HIV. A ƙarshe, ana tunanin cewa DNA ligase enzymes sun haɗa da sauran ɓangaren da ba a ɗaure ba na HIV da kuma jigilar DNA. A halin yanzu wannan tsarin yana da inganci sosai ta gwaji kuma yanki ne da ake bincike. Wannan tsari na gyaran gibi ya kammala haɗa DNA ɗin HIV cikin DNA ɗin da ke gida, tare da cikakken haɗin DNA na HIV yanzu ana kiransa "DNA Proviral".
Matsayin splicing a cikin HIV-1
[gyara sashe | gyara masomin]Binciken da aka yi kwanan nan ya ba da shawarar cewa HIV-1 ya fi son haɗuwa cikin kwayoyin halitta ko kwayoyin halitta tare da ƙarin introns.[2] Wannan fifiko ya dogara da furotin mai ɗaure chromatin LEDGF / p75 wanda ke hulɗa da abubuwa masu yawa.[2] Wani binciken ya nuna cewa fifiko na HIV-1 ga kwayoyin halitta masu haɗuwa sosai ya dogara da wani abu mai masaukin CPSF6, wani abu mai suna poly adenylation.[3] Kwayoyin cutar kansa tare da adadi mai yawa na introns suna da niyya sosai ta hanyar HIV-1.[2]
- ↑ Smith JA, Nunnari G, Preuss M, Pomerantz RJ, Daniel R (2007). "Pentoxifylline suppresses transduction by HIV-1-based vectors". Intervirology. 50 (5): 377–86. doi:10.1159/000109752. PMID 17938572. S2CID 34357038.
- ↑ 2.0 2.1 2.2 Singh, Parmit Kumar; Plumb R., Matthew; Ferris, Andrea L.; Iben, James R.; Wu, Xiaolin; Fadel, Hind J.; Luke, Brian T.; Esnault, Caroline; Poeschla, Eric M. (2015). "LEDGF/p75 interacts with mRNA splicing factors and targets HIV-1 integration to highly spliced genes". Genes Dev. 29 (21): 2287–97. doi:10.1101/gad.267609.115. PMC 4647561. PMID 26545813.
- ↑ Sowd GA, Serrao E, Wang H, Wang W, Fadel HJ, Poeschla EM, et al. (2016). "A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin". Proc Natl Acad Sci U S A. 113 (8): E1054–63. Bibcode:2016PNAS..113E1054S. doi:10.1073/pnas.1524213113. PMC 4776470. PMID 26858452.