ATAD5 deficiency decreases B cell division and Igh recombination (IRM8P.700)

Abstract

Abstract Mammalian ATAD5 and its yeast homolog ELG1 are responsible for unloading PCNA 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 PCNA and slower cell division. We used B cells from heterozygous (Atad5+/m) mice to examine the effects of PCNA buildup and decreased cell proliferation on antibody diversity. ATAD5 haploinsufficiency did not affect the frequency or spectrum of somatic hypermutation in antibody genes from Peyer’s patch B cells, indicating that PCNA accumulation did not alter DNA repair or DNA polymerase η usage at the Igh locus. However, following ex vivo stimulation, Atad5+/m B cells were delayed during S-phase cell cycle progression and had reduced cell proliferation compared to wild type cells. These cells had a significant decline in activation-induced deaminase expression, resulting in decreased double-strand breaks in the switch region and inter-chromosomal translocations. Class switch recombination was also reduced, although the types of end-joining pathways were not affected. Our results describe a defect in DNA replication that directly affects Igh recombination via reduced cell division.