title: ATAD5 deficiency decreases B cell division and Igh recombination.
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 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.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Zanotti
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Maul
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and.
authors.forename: Diana P
authors.initials: DP
authors.lastname: Castiblanco
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and.
authors.forename: William
authors.initials: W
authors.lastname: Yang
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yong Jun
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Fox
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kyungjae
authors.initials: K
authors.lastname: Myung
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and huseyin.saribasak@sifa.edu.tr gearhartp@mail.nih.gov.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Saribasak
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and huseyin.saribasak@sifa.edu.tr gearhartp@mail.nih.gov.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gearhart
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D000916:Antibody Diversity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D018809:Proliferating Cell Nuclear Antigen; D003564:Cytidine Deaminase; C000595579:ATAD5 protein, mouse; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities