Document Detail


ATAD5 Deficiency Decreases B Cell Division and Igh Recombination.
MedLine Citation:
PMID:  25404367     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Mammalian ATPase family AAA domain-containing protein 5 (ATAD5) and its yeast homolog enhanced level of genomic instability 1 are responsible for unloading proliferating cell nuclear antigen from newly synthesized DNA. Prior work in HeLa and yeast cells showed that a decrease in ATAD5 protein levels resulted in accumulation of chromatin-bound proliferating cell nuclear antigen, slowed cell division, and increased genomic instability. In this study, B cells from heterozygous (Atad5(+/m)) mice were used to examine the effects of decreased cell proliferation on Ab diversity. ATAD5 haploinsufficiency did not change the frequency or spectrum of somatic hypermutation in Ab genes, indicating that DNA repair and error-prone DNA polymerase η usage were unaffected. However, immunized Atad5(+/m) mice had decreased serum IgG1 Abs, demonstrating a functional effect on class switch recombination. The mechanism of this altered immune response was then examined following ex vivo stimulation of splenic B cells, where Atad5(+/m) cells accumulated in the S phase of the cell cycle and had reduced proliferation compared with wild-type cells. These haploinsufficient cells underwent a significant decline in activation-induced deaminase expression, resulting in decreased switch region DNA double-strand breaks and interchromosomal translocations in the Igh locus. Class switch recombination to several isotypes was also reduced in Atad5(+/m) cells, although the types of end-joining pathways were not affected. These results describe a defect in DNA replication that affects Igh recombination via reduced cell division.
Authors:
Kimberly J Zanotti; Robert W Maul; Diana P Castiblanco; William Yang; Yong Jun Choi; Jennifer T Fox; Kyungjae Myung; Huseyin Saribasak; Patricia J Gearhart
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-17
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  -     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-18     Completed Date:  -     Revised Date:  2014-11-19    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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