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Myung, Kyungjae
Center for Genomic Integrity
Research Interests
  • DNA Replication, DNA Repair, DNA Recombination, DNA Damage Response, cancer, aging

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ATAD5 deficiency decreases B-cell division and Igh recombination

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Title
ATAD5 deficiency decreases B-cell division and Igh recombination
Author
Zanotti, Kimberly J.Maul, Robert W.Yang, WilliamChoi, YongjunFox, JenniferMyung, KyungjaeSaribasak, HuseyinGearhart, Patricia J.
Keywords
CLASS-SWITCH RECOMBINATION; DNA-POLYMERASE-ETA; INDUCED CYTIDINE DEAMINASE; END-JOINING PATHWAYS; DOUBLE-STRAND BREAKS; SOMATIC HYPERMUTATION; ANTIBODY DIVERSIFICATION; IMMUNOGLOBULIN GENES; VARIABLE GENES; PCNA
Issue Date
2015-01
Publisher
AMER ASSOC IMMUNOLOGISTS
Citation
JOURNAL OF IMMUNOLOGY, v.194, no.1, pp.35 - 42
Abstract
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 eta 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.
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DOI
10.4049/jimmunol.1401158
ISSN
0022-1767
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BME_Journal Papers
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