AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.

Abstract:

:To initiate class switch recombination (CSR) activation-induced cytidine deaminase (AID) induces staggered nick cleavage in the S region, which lies 5' to each Ig constant region gene and is rich in palindromic sequences. Topoisomerase 1 (Top1) controls the supercoiling of DNA by nicking, rotating, and religating one strand of DNA. Curiously, Top1 reduction or AID overexpression causes the genomic instability. Here, we report that the inactivation of Top1 by its specific inhibitor camptothecin drastically blocked both the S region cleavage and CSR, indicating that Top1 is responsible for the S region cleavage in CSR. Surprisingly, AID expression suppressed Top1 mRNA translation and reduced its protein level. In addition, the decrease in the Top1 protein by RNA-mediated knockdown augmented the AID-dependent S region cleavage, as well as CSR. Furthermore, Top1 reduction altered DNA structure of the Smu region. Taken together, AID-induced Top1 reduction alters S region DNA structure probably to non-B form, on which Top1 can introduce nicks but cannot religate, resulting in S region cleavage.

authors

Kobayashi M,Aida M,Nagaoka H,Begum NA,Kitawaki Y,Nakata M,Stanlie A,Doi T,Kato L,Okazaki IM,Shinkura R,Muramatsu M,Kinoshita K,Honjo T

doi

10.1073/pnas.0911879106

subject

Has Abstract

pub_date

2009-12-29 00:00:00

pages

22375-80

issue

52

eissn

0027-8424

issn

1091-6490

pii

0911879106

journal_volume

106

pub_type

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