Ibiyobyabwengethalidomideyibukijwe mu myaka ya za 1960 kubera ko yateje inenge zikomeye ku bana bavutse, ariko icyarimwe ikaba yarakoreshejwe cyane mu kuvura sclerose nyinshi na kanseri y’amaraso, kandi irashobora, hamwe na benewabo b’imiti, bishobora guteza imbere ingirabuzimafatizo za poroteyine ebyiri zihariye zigize abanyamuryango. umuryango wa poroteyine zisanzwe "zidafite ibiyobyabwenge" (ibintu byandikirwa) bifite imiterere yihariye ya molekile, C2H2 zinc urutoki.

Mu bushakashatsi buherutse gusohoka mu kinyamakuru mpuzamahanga cyitwa Science, abahanga bo mu kigo cya MIT Boulder ndetse n’ibindi bigo basanze thalidomide n’ibiyobyabwenge bifitanye isano bishobora gutanga intangiriro y’abashakashatsi kugira ngo bashake ubwoko bushya bw’imiti irwanya kanseri biteganijwe ko bugera kuri 800 ibintu byo kwandukura bisangiye motif imwe. Impapuro zandikirana zihuza ADN kandi igahuza imvugo ya genes nyinshi, akenshi zihariye ubwoko bwimikorere cyangwa ingirabuzimafatizo; izo poroteyine zifitanye isano na kanseri nyinshi iyo zigenda nabi, ariko abashakashatsi basanze bishobora kuba bigoye kubatera intego yo guteza imbere ibiyobyabwenge kuko ibintu byandikirwa akenshi bibura aho molekile zibiyobyabwenge zihurira nazo.

Thalidomide na bene wabo ba shimi pomalidomide na lenalidomide barashobora kwibasira mu buryo butaziguye intego zabo bashakisha poroteyine yitwa cereblon - ibintu bibiri byandikirana bifite C2H2 ZF: IKZF1 na IKZF3. Cereblon ni molekile yihariye yitwa E3 ubiquitin ligase kandi irashobora gushiraho poroteyine zihariye zo kwangirika na sisitemu yo gutembera kwa selile. Mugihe thalidomide na benewabo badahari, cereblon yirengagije IKZF1 na IKZF3; imbere yabo, iteza imbere kumenya ibyo bintu byandikirwa hamwe nibirango byo gutunganya.

Uruhare rushya kuriiyikeraibiyobyabwenge

Ikiremwamuntu gifite ubushobozi bwo gushiramo ibintu 800 byandikirwa, nka IKZF1 na IKZF3, zishobora kwihanganira ihinduka ry’imihindagurikire ya C2H2 ZF; kumenya ibintu byihariye bishobora gufasha mugutezimbere ibiyobyabwenge birashobora gufasha abashakashatsi kuvumbura niba izindi mpamvu zisa na transcription zishobora kwanduzwa nibiyobyabwenge nka thalidomide. Niba hari imiti isa na thalidomide yari ihari, abashakashatsi bashoboraga kumenya neza neza C2H2 ZF imitungo ya proteine ​​cereblon, hanyuma igasuzuma ubushobozi bwathalidomide, pomalidomide na lenalidomide kugirango itere kwangirika kwa 6.572 yihariye ya C2H2 ZF ya motif ya moderi ya selile. Amaherezo, abashakashatsi bagaragaje poroteyine esheshatu C2H2 ZF zirimo kumva izo miti, enye muri zo ntizigeze zifatwa nk’ibasirwa na thalidomide na bene wabo.

Abashakashatsi bahise bakora imikorere nuburyo IKZF1 na IKZF3 kugirango basobanukirwe neza nuburyo bwimikoranire hagati yimpapuro zandikirwa, cereblon na thalidomide. Uretse ibyo, banakoresheje imashini ya mudasobwa 4,661 kugira ngo barebe niba izindi mpamvu zishobora kwandikirwa hamwe na cereblon imbere y’ibiyobyabwenge. Abashakashatsi berekanye ko imiti ihinduwe neza ya thalidomide igomba gutera cereblon kuranga isoforms yihariye ya C2H2 ZF yo kwandukura.