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AID-initiated DNA lesions are differentially processed in distinct B cell populations.

ABSTRACT: Activation-induced deaminase (AID) initiates U:G mismatches, causing point mutations or DNA double-stranded breaks at Ig loci. How AID-initiated lesions are prevented from inducing genome-wide damage remains elusive. A differential DNA repair mechanism might protect certain non-Ig loci such as c-myc from AID attack. However, determinants regulating such protective mechanisms are largely unknown. To test whether target DNA sequences modulate protective mechanisms via altering the processing manner of AID-initiated lesions, we established a knock-in model by inserting an S?2b region, a bona fide AID target, into the first intron of c-myc. Unexpectedly, we found that the inserted S region did not mutate or enhance c-myc genomic instability, due to error-free repair of AID-initiated lesions, in Ag-stimulated germinal center B cells. In contrast, in vitro cytokine-activated B cells display a much higher level of c-myc genomic instability in an AID- and S region-dependent manner. Furthermore, we observe a comparable frequency of AID deamination events between the c-myc intronic sequence and inserted S region in different B cell populations, demonstrating a similar frequency of AID targeting. Thus, our study reveals a clear difference between germinal center and cytokine-activated B cells in their ability to develop genomic instability, attributable to a differential processing of AID-initiated lesions in distinct B cell populations. We propose that locus-specific regulatory mechanisms (e.g., transcription) appear to not only override the effects of S region sequence on AID targeting frequency but also influence the repair manner of AID-initiated lesions.

SUBMITTER: Chen Z

PROVIDER: S-EPMC4239163 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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AID-initiated DNA lesions are differentially processed in distinct B cell populations.

Chen Zhangguo Z Ranganath Sheila S Viboolsittiseri Sawanee S SS Eder Maxwell D MD Chen Xiaomi X Elos Mihret T MT Yuan Shunzong S Hansen Erica E Wang Jing H JH

Journal of immunology (Baltimore, Md. : 1950) 20141022 11

Activation-induced deaminase (AID) initiates U:G mismatches, causing point mutations or DNA double-stranded breaks at Ig loci. How AID-initiated lesions are prevented from inducing genome-wide damage remains elusive. A differential DNA repair mechanism might protect certain non-Ig loci such as c-myc from AID attack. However, determinants regulating such protective mechanisms are largely unknown. To test whether target DNA sequences modulate protective mechanisms via altering the processing manne ...[more]

PMID: 25339658

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Dataset Information

AID-initiated DNA lesions are differentially processed in distinct B cell populations.

Publications

AID-initiated DNA lesions are differentially processed in distinct B cell populations.

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