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Skewing the Playing Field: A Single-Molecule Study on how RSS Sequence Influences Gene Segment Selection

Hirokawa, Soichi and Belliveau, Nathan M. and Lovely, Geoffrey A. and Anaya, Michael and Schatz, David G. and Baltimore, David and Phillips, Rob (2018) Skewing the Playing Field: A Single-Molecule Study on how RSS Sequence Influences Gene Segment Selection. Biophysical Journal, 114 (3). 86a. ISSN 0006-3495. https://resolver.caltech.edu/CaltechAUTHORS:20180510-124207785

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Abstract

V(D)J recombination, the cut-and-paste process that combines various antibody-encoding gene segments, provides jawed vertebrates with a combinatorically diverse arsenal of unique antibodies that allows the organism to identify virtually any invading bacterium or infected cell. To initiate this process, the RAG enzymatic complex binds two recognizable recombination signal sequences (RSSs) neighboring the gene segments and subsequently cleaves the DNA to expose the segments before additional enzymes join the two ends to create a continuous antibody-encoding gene. While the general process is well understood, the root causes for the non-uniform distribution of gene segment selection have not been clearly parsed out. In this project, we examine how the sequence diversity of RSSs affect RAG's affinity for forming paired complexes and its propensity for cleaving the DNA, the two key steps for passing two gene segments onward to generate an antibody-encoding gene. Using a single-molecule method known as tethered particle motion (TPM), we systemically study a range of RSS sequences, from single mutation deviations away from the consensus sequence to endogenous RSSs, to determine that RSS sequence is a significant determinant for whether a given gene segment in any antibody gene loci will be selected to produce an antibody. We expect that this work will set us on an initial path to better understanding how the dynamic nature of the genome influences the likelihood that a lymphocyte will produce a particular antibody.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.bpj.2017.11.511DOIArticle
ORCID:
AuthorORCID
Hirokawa, Soichi0000-0001-5584-2676
Belliveau, Nathan M.0000-0002-1536-1963
Anaya, Michael0000-0002-6944-3614
Baltimore, David0000-0001-8723-8190
Phillips, Rob0000-0003-3082-2809
Additional Information:© 2018 Elsevier Inc. Available online 6 February 2018.
Issue or Number:3
Record Number:CaltechAUTHORS:20180510-124207785
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180510-124207785
Official Citation:Skewing the Playing Field: A Single-Molecule Study on how RSS Sequence Influences Gene Segment Selection Hirokawa, Soichi et al. Biophysical Journal , Volume 114 , Issue 3 , 86a
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86337
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 May 2018 20:57
Last Modified:09 Mar 2020 13:18

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