Alu序列介导肿瘤中反复发生的染色体畸变

?310? ???? : 2003 - 12 - 05 ; ???? : 2004 - 02 - 10 ???? : ??? (1974 - ) ,? ,???? ,????? ,???? :?????。 Tel : 021 - 25070301 ; E - mail : houqiliu @hotmail . com ?? ??? ??? Carcinogenesis , Teratogenesis and Mutagenesis ? 16? ? 5? Vol. 16 No. 5 2004? 9? Spet , 2004 ??? ? Alu ????????????????? ??? , ??? ?? ??? ?? (?????????????? , ?? 200433) 【??】??????????????? ,?? DNA???????????????。?????? ,? Alu?? ,???? ??????????????????????????????????????? , ????????????? ?。??? ,? X?? (X?????? Escherichia coli ? recBCD?????)????? Alu??????????? DNA? ????????。????????????????????/??? ,Alu ???????????????????? ????。???????????????????? , ????????????????? , ??????????? ??????。?????????????????? Alu ???????????? 。 【???】Alu?? ; ??? ; ?? ????? : R730. 2 ????? : A ???? : 1004 - 616X(2004) 05 - 0310 - 05 ???????????? , ??????????? ?????? (??、??、??) 。????、?????? ? , ??????????????????????? ?。??????????????? ,????????? ? ,??????????????????。?????? ?? , ??????????????????????? ?? : V(D) J ?? , Alu?????????、translin??、 Z-DNA???????、????? Ⅱ?????、???? ??????????? (NHEJ) ????? DNA???? ??????。??????????? , ??????? ???????????????????????? [1 ]。 1 ???????????? ?????????????????????? , ? ????????????????。??????? ,?? ????????? V(D) J ?????? heoptamer/ nonamer ????? [2 ,3 ]???????。???????????? V(D) J ????????。?????????? ,???? ????????????。????????? Alu??? ?????????????????????????? ????。?? , ?????????????????? , ??????????? translin??? DNA?????? (translin???? DNA?????) , ?????????? ????? [4 ]。 ?????????????????????。??? ? , ???????????????????????啶? ? [5 ,6 ]?? ,????????致??????? (Z-DNA) ?? ?。????????????????????????? ???。??? , ???????? Ⅱ???????? DNA ??????????????????? [7 ,8 ]。?????? ??????????????????????????。 ?????? ,???????????? [9?11 ] ,?????? ??????????????? [12 ]。???? ,?????? ??????????致????????? , ?????? ?? [13 ]。DNA?????? ,???????? ,?????? ????????????????? DNA????? [14 ,15 ]。 2 ??????????? ?????? ,DNA??????致????。DNA?? ???????????。?? DNA????? ,????? ????????? : ??????? (NHEJ) 、???? (HR)?????。????????????????? ,? ????????????? HR [1 6 ]? NHEJ [1 7 ]。????? ??????? DNA????????????????? ??????????? , ????? DNA?? (DSBs) 。? ? , ? DNA?????????? DSBs ;??? DNA??? ???? (?????????) ?????? DSB S[10 ] , ?? ???????。?????????????????? ?? DSBs????????。????????????? ??????????? DNA???????。 ? Escheridia coli ? ,至? 25????? HR??。??? ??? : RecA ,RecBCD ,RecF ,-G,-J ,-N ,DNA??? , DNA?? ?311 ? ???? DNA????。?????????、?????至 ????????? 。RecA? RecBCD????? X ??? ???。X???????、????????? ,? Rec ?? ??? DNA ???????? 。RecBCD ????? Es2 cheridia coli ? DSBs????? HR????? , ????? ? DNA?????。RecBCD???????? ,??? DNA (ssDNA) ???、?????? DNA(dsDNA) ??????? ?????。RecBCD ?????? ssDNA??????? ssDNA [1 8 ] 。??????? X??? RecBCD? 3‘-5’???? ??? ,???????? [19 ]。X????? RecBCD? DNA ????????????? , ?? X????????? ???????? RecBCD??????????? ,??? ? RecBCD????? [20 ]。???? RecD?? ,RecBCD?? ??????? , ?? RecA??? X??? ssDNA?? , ? ??????????? [18 ]。????? ssDNA????? ? DNA??????????? DSB????。RecA??? ??? Escherichia coli ?????????? , ????? X ???? [21 ]。RecA??? DNA??????????? ,? ???????? DNA????? X????????? ????????????????。?? RecA????? ? DNA??????????? ,????????? [2 2 ] 。 3 ?????????? ?????? ,HR??????? DNA???。??? ? HR?? DSBs ?????? RAD????? (????? ???????? [14 ]) 。HR????????? : ???? DNA? DNA????。???????????????? ??????????。 ?? E. coli ? RecA?? S. cerevisiae ?? Rad51?? , ? ????????????? Rad51???? [23 ]????? ?????? , HR???????? RecA??????? ??。RecA、Rab51????? Rad51???????? DNA ???????????? DNA [24 ]。? Rad51?????? ??????????????? Rad51?????? RecA ??????????? [25 ]。??????????? 7? RecA???。????????????? ,??????? ????? : Rad51 ,Dmc1? Rad55-57 [2 5 ]。?? , Rad51??? ???????????????????????? [26 ] , ? Dmc1????????????? [2 7 ,28 ] ;??????? ????? DNA?????????????。???? Rad51??? , ????????????? Rad51???? ? 。?? ssDNA?????? , RPA???? Rad51??? DNA???????? ,???????? Rad51? [25 ]。RPA ???????? Rad52??? [29 ]。?? Rad51? DNA?? ??? Rad52??? DNA?? [3 0 ]。in vitro ??? , Rad51 ? ???? DNA???? Rad51? Rad54(dsDNA?? ATP ? , ?? Swiz/ Sngz???) ????? [2 4 ,31 ] , ?? Rad54 ??? Rad51??? DNA???? DNA??。??? RecA ,Rad51? ? ssDNA??????????? , ?????????? ??? DNA????。???? dsDNA、???????? Mre11 ,Rad51? Nibrin/ p95/ NBS??????????? [32 ]。 ???? Rad51????????????????? ?????????? HR ??。?????? : BRCA1 ? BRCA2???? [33 ]、ABL [3 4 ]? TP53 [3 5 ]???。?????? ????????????? DNA????????? 。 Rad51? HR?? DNA?????????。??????? ???????????? [2 5 ]。???????????? ??? DSBs?????????????。??????? ???????????????? HR??? ,????? ??????????????????。 4 HR? NHEJ ? dsD NA?????????? ?????????? , ????????? , ? DSBs ??????????? [36 ]。?????? , DSBs???? ?? : HR? NHEJ ????????? (????????? ????) 。?????????? DNA????????? ?????????? [37 ]。?????????????? ??????。HR????????? , ???????? ????????????? (? Alu???) ?????? ???? , ????????????????????? ??。???? ,??????????????????? ? [38 ] , ??????????????????????? ????????????? 5 000? [3 6 ]。 ? HR?? ,NHEJ ???????????? ,???? ????? , ???????? 。??? NHEJ ????? ?????????? : ??? DNA????????? (DNA-PK) ,?????? , Ku70 , Ku80? DNA-PK????? ? (DNA-PKcs) ; ???? DNA??? IV? XRCC4?? [39 ]。 Ku???? Ku70? Ku80???????? ,?? DNA?? ????? DNA-Pkcs? DSBs??? ,??????? ,?? ???????? [40 ] 。????????? , ?????? ???????????????????? , HR? NHEJ ????????? [41 ]。????? HR? NHEJ ????? ?????????????? , ??????????? ??????。HR??? S-G2 ? ,? NHEJ ?? G1- ? S?? ???? [42 ]。??? , HR ? G2 ???????????? ? , ????????????? , ?????????? ???? [36 ]。???????? , ? G1 ??? HR ??? NHEJ ??????? [4 3 ]。???????? ,NHEJ ? HR? ?? DSBs??????? ,???????????? [44 ]。 5 Alu????????? ? 1/ 3???????????????? , ???? ???????????????? 。?????? SINE ?????? RNA ???????? 。Alu ?????? SINE?????? , ????????????? 100?10 4 ??? [4 5 ]。??????? Alu ???? 5 %?10 % , ? ?? 4 kb????? Alu ?? , ??????? Alu ??? ?????? [46 ]。?????????? Alu?????? ??? R????? [4 7 ]。??????????? Alu?? ? 5? ???? Alu????????????????? ?312? ??? GC??? AT?????? [4 5 , 46 ] , ?? Alu ???? ?? R??????。?? Alu??????????? ,? ?????????????????????????? ???? [4 6 ]。???? Alu???? GC???????? DNA????? 9? , ?????? Alu ???????? ????????? [48 ]。?? Alu??????????? ? ,??? 70 %?98 %?????。?? 282 bp ????? ???????? 5‘?? , ????????????? ?。???????? A????? [49 ] , ???? 7SL RNA ?? ( 7SL RNA??????????) 。Alu???? RNA ??? III? A-box? B-box??? , ???? in vitro ??? ????。 ??????????????????? , ???? Alu?????? 26 bp ??????????????? ??? ( 25?50 bp) [50 ]。???????? Alu?????? ??? DNA????????????。Alu ?????? E. coli ??? RecBCD ????? X?????。???? Alu???????????????? HR ?????? ??? 。????????? Alu ????????? Translin?????????????? , ???????? ?? [5 1 ]。Translin?????????????? DNA??? ?。?? Translin??????????????????? ????????????? [4 ]。?? Translin?????? ?????? Alu?????。????????、???? ??????? DNA?? DSBs???????????? Alu????????????? 。??????? ,?? Alu ????????? , ???????????????? ???? ,????? RAD?????????。????? ??? , Alu?????????? , ?????? HR?? ?。? Alu????????????????? ,???? ??????????????? [52 ] , ? Alu?????? ????????????致。?? Alu????????? ?????? (in sis) ,????????????? ;??? ?????? (i n trans) , ??????????????? ???? [5 3 ] 。?????????? Alu ??????? , ??? HR???????????致??????? [5 4 ] 。 ??? 16? Alu??????????????????? ???? [53 ] , ????? Alu ??????致 0. 1 %??? ???? [54 ]。Alu??????????????????? ?????? : ?? CML?? Philadelphia ?? , ????? BCR/ ABL1?? [5 5 ] , Ph?? ALL [5 6 ] ??????????? ?????? MLL??。??????????????? ????? Alu?????? ,????? in vivo ??? ,? ???? Alu ???????????????。 6 ?????????????????? ? 10 %????? ,??????????????? ???? [57 ]。?????? 250???????? CML?? ?? 13? Ph + ALL?????????? , ?????? ?? 23? CML (9. 2 %) ?? 1? ALL(7. 7 %) ???? ABL ????? BCR?????????? 。???????? ?????????????????????? , ??? ????????????。????????????? ?????? , ??????????????????? ?????致?。?????????????????? ?????? ,?????????。??????? Censor ? Repeat Masker ??????????????????? ? DNA??????。??????????????? Alu?????????????? 。? t( 9 , 22) (ABL ? BCR) ?? inv( 16) (CBFB ? MYHn) ? DNA????? Alu ? ??????? t (15: 17) (PML? RARA) 。? BCR? ABL? ?? Alu????????????? , ??? 5’???? ????? [5 8 ]。?? ,????? Alu?????????? ??? [59 ] 。??????? Alu???????????? ???。?????? ,???????????????? Alu????????????????????????。 Sinclair ????? 9? 22???????????? ???????? [60 ]。?????????????? bp ? ? ,???????。?????? ,??? DSBs? ,??? ???????????????? bp????? [61 ]。?? ????????????????? (11- 18bp ????? ??) , ???????????? , ??? DNA????? ? [62 ]。Alu??????????????? [63 ] ,????? ??????????? [64 ]。?? Alu????????? , ???????? Alu??????????? ,????? ?????。???????????? ,???????? ?????????? Alu?????????致???? ??????。????? DSBs?? ,Alu???????? ???????????????????????? , ? ???????? HR???。????? ,??????? ?????????? ,?????? [65 ]。???????? ? , ??????????????? BCR? ABL???? ????? ,?? Alu????????? [6 6 ]。 ???? : [ 1] Aplan PD. Mechanism of leukemogenesis : Chromosomal t ranslocations [C]. American Society of Hematology annualmeeting. 1999. 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