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The role of E boxes and other DNA el...

McDonald, Jessica Jane.

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The role of E boxes and other DNA elements in the targeting of somatic hypermutation.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	The role of E boxes and other DNA elements in the targeting of somatic hypermutation./
作者:	McDonald, Jessica Jane.
面頁冊數:	116 p.
附註:	Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
Contained By:	Dissertation Abstracts International74-11B(E).
標題:	Health Sciences, Immunology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3572038
ISBN:	9781303299520

The role of E boxes and other DNA elements in the targeting of somatic hypermutation.
McDonald, Jessica Jane.

The role of E boxes and other DNA elements in the targeting of somatic hypermutation. - 116 p.

Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.

Thesis (Ph.D.)--Yale University, 2013.

Secondary B cell repertoire diversification occurs by somatic hypermutation (SHM) in germinal centers following antigen stimulation. In SHM, activation-induced cytidine deaminase (AID) mutates the variable region of the immunoglobulin (Ig) genes to increase the affinity of antibodies. Although AID acts primarily at the Ig loci, low levels of off-target mutation can result in oncogenic DNA damage, emphasizing the need to understand how SHM targeting is achieved.

ISBN: 9781303299520Subjects--Topical Terms:

1017716
Health Sciences, Immunology.

The role of E boxes and other DNA elements in the targeting of somatic hypermutation.
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245 1 4 $a The role of E boxes and other DNA elements in the targeting of somatic hypermutation.
300 $a 116 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
500 $a Adviser: David G. Schatz.
502 $a Thesis (Ph.D.)--Yale University, 2013.
520 $a Secondary B cell repertoire diversification occurs by somatic hypermutation (SHM) in germinal centers following antigen stimulation. In SHM, activation-induced cytidine deaminase (AID) mutates the variable region of the immunoglobulin (Ig) genes to increase the affinity of antibodies. Although AID acts primarily at the Ig loci, low levels of off-target mutation can result in oncogenic DNA damage, emphasizing the need to understand how SHM targeting is achieved.
520 $a Using a reporter cassette introduced into the Ig light chain ( IgL) of chicken DT40 B cells to assay cis-acting DNA elements for SHM targeting, I have helped identify a 1.9- kb region of the downstream IgL sequences capable of stimulating AID-dependent mutation. Further investigation of this diversification activator (DIVAC) element by deletion analysis has demonstrated that while targeting activity is broadly dispersed, two 'core' regions are required for full activity: a 200-bp section of the enhancer and a 350-bp region downstream.
520 $a Despite substantial progress in localizing DIVAC activity, it has been unclear what individual DNA binding motifs, if any, might be functioning to promote SHM targeting. One candidate is the E box, a 6-bp DNA sequence found in many AID target genes, but which has yet to be shown to be important in directing mutation to endogenous Ig loci. Point mutation of all 20 E boxes in the 1.9-kb composite fragment reduced SHM targeting activity by 90%, and to date is the largest documented role for any single motif in the targeting of SHM. Mutation of subsets of the E boxes identified a functional hierarchy in which E boxes within the core regions were of greatest importance. Strikingly, when the sequence and spacing of the 20 E boxes was preserved but all surrounding sequences were scrambled, SHM targeting activity dropped to background levels. Hence, while E box motifs are vital SHM targeting elements, their function is completely dependent on their surrounding sequence context.
520 $a This work is the first to show that the E box is a key sequence for SHM targeting within a highly active element, and to clarify that this motif cannot act independently. These two findings suggest that SHM targeting to the Ig loci relies on an intimate cooperation between E boxes and other sequence motifs, thereby explaining how a common DNA element could function as part of a specific targeting mechanism, and also potentially providing insight into how mistargeting to non-Ig loci occurs.
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