A -Acting Diversification Activator Both Necessary and Sufficient for AID-Mediated Hypermutation

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Hypermutation of the immunoglobulin (Ig) genes requires Activation Induced cytidine Deaminase (AID) and transcription, but it remains unclear why other transcribed genes of B cells do not mutate. We describe a reporter transgene crippled by hypermutation when inserted into or near the Ig light chain (IgL) locus of the DT40 B cell line yet stably expressed when inserted into other chromosomal positions. Step-wise deletions of the IgL locus revealed that a sequence extending for 9.8 kilobases downstream of the IgL transcription start site confers the hypermutation activity. This sequence, named DIVAC for diversification activator, efficiently activates hypermutation when inserted at non-Ig loci. The results significantly extend previously reported findings on AID-mediated gene diversification. They show by both deletion and insertion analyses that cis-acting sequences predispose neighboring transcription units to hypermutation.

Vyšlo v časopise: A -Acting Diversification Activator Both Necessary and Sufficient for AID-Mediated Hypermutation. PLoS Genet 5(1): e32767. doi:10.1371/journal.pgen.1000332
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000332

Souhrn

Zdroje

1. MuramatsuM

KinoshitaK

FagarasanS

YamadaS

ShinkaiY

2000 Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102 553 563

2. ArakawaH

HauschildJ

BuersteddeJM

2002 Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion. Science 295 1301 1306

3. HarrisRS

SaleJE

Petersen-MahrtSK

NeubergerMS

2002 AID is essential for immunoglobulin V gene conversion in a cultured B cell line. Curr Biol 12 435 438

4. Di NoiaJ

NeubergerMS

2002 Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419 43 48

5. RadaC

Di NoiaJM

NeubergerMS

2004 Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol Cell 16 163 171

6. PetersA

StorbU

1996 Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4 57 65

7. ShinkuraR

TianM

SmithM

ChuaK

FujiwaraY

2003 The influence of transcriptional orientation on endogenous switch region function. Nat Immunol 4 435 441

8. ShenHM

PetersA

BaronB

ZhuX

StorbU

1998 Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280 1750 1752

9. LiuM

DukeJL

RichterDJ

VinuesaCG

GoodnowCC

2008 Two levels of protection for the B cell genome during somatic hypermutation. Nature 451 841 845

10. OdegardVH

SchatzDG

2006 Targeting of somatic hypermutation. Nat Rev Immunol 6 573 583

11. BetzAG

MilsteinC

González-FernándezA

PannellR

LarsonT

1994 Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region. Cell 77 239 248

12. KlotzEL

StorbU

1996 Somatic hypermutation of a lambda 2 transgene under the control of the lambda enhancer or the heavy chain intron enhancer. J Immunol 157 4458 4463

13. KlixN

JollyCJ

DaviesSL

BrüggemannM

WilliamsGT

1998 Multiple sequences from downstream of the Jκ cluster can combine to recruit somatic hypermutation to a heterologous, upstream mutation domain. Eur J Immunol 28 317 326

14. KongQ

ZhaoL

SubbaiahS

MaizelsN

1998 A λ 3′ enhancer drives active and untemplated somatic hypermutation of a λ1 transgene. J Immunol 161 294 301

15. van der StoepN

GormanJR

AltFW

1998 Reevaluation of 3′Eκ function in stage- and lineage-specific rearrangement and somatic hypermutation. Immunity 8 743 750

16. InlayMA

GaoHH

OdegardVH

LinT

SchatzDG

2006 Roles of the Igκ light chain intronic and 3′ enhancers in Igk somatic hypermutation. J Immunol 177 1146 1151

17. WangCL

HarperRA

WablM

2004 Genome-wide somatic hypermutation. Proc Natl Acad Sci U S A 101 7352 7356

18. YoshikawaK

OkazakiIM

EtoT

KinoshitaK

MuramatsuM

2002 AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296 2033 2036

19. ArakawaH

SaribasakH

BuersteddeJM

2004 Activation-induced cytidine deaminase initiates immunoglobulin gene conversion and hypermutation by a common intermediate. PLoS Biol 2 e179 doi:10.1371/journal.pbio.0020179

20. ArakawaH

KudoH

BatrakV

CaldwellRB

RiegerMA

2008 Protein evolution by hypermutation and selection in the B cell line DT40. Nucleic Acids Res 36 e1

21. GopalAR

FugmannSD

2008 AID-mediated diversification within the IgL locus of chicken DT40 cells is restricted to the transcribed IgL gene. Mol Immunol 45 2062 2068

22. International Chicken Genome Sequencing Consortium 2004 Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432 695 716

23. SaleJ

NeubergerMS

1998 TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity 9 859 869

24. ZhangW

BardwellPD

WooCJ

PoltoratskyV

ScharffMD

2001 Clonal instability of V region hypermutation in the Ramos Burkitt's lymphoma cell line. Int Immunol 13 1175 1184

25. Bulfone-PausS

Reiners-SchrammL

LausterR

1995 The chicken immunoglobulin lambda light chain gene is transcriptionally controlled by a modularly organized enhancer and an octamer-dependent silencer. Nucleic Acids Res 23 1997 2005

26. KothapalliN

NortonDD

FugmannSD

2008 Cutting edge: a cis-acting DNA element targets AID-mediated sequence diversification to the chicken Ig light chain gene locus. J Immunol 180 2019 2023

27. NagaokaH

MuramatsuM

YamamuraN

KinoshitaK

HonjoT

2002 Activation-induced deaminase (AID)-directed hypermutation in the immunoglobulin Smu region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation. J Exp Med 195 529 534

28. ArakawaH

LodyginD

BuersteddeJM

2001 Mutant loxP vectors for selectable marker recycle and conditional knock-outs. BMC Biotechnol 1 7

29. HamimesS

ArakawaH

StasiakAZ

KierzekAM

HiranoS

2004 RDM1, a novel RNA recognition motif (RRM)-containing protein involved in the cell response to cisplatin in vertebrates. J Biol Chem 280 9225 9235

30. BuersteddeJM

TakedaS

1991 Increased ratio of targeted to random integration after transfection of chicken B cell lines. Cell 67 179 188