title: Altered pattern of immunoglobulin hypermutation in mice deficient in Slip-GC protein.
abstract: We recently identified a novel germinal center GTPase, SLIP-GC, that localizes to replication factories in B cells and that, when reduced, induces DNA breaks in lymphoma B cell lines in an activation-induced deaminase (AID)-dependent manner. Herein, we generated mice deficient in SLIP-GC and examined the impact of SLIP-GC deficiency in immunoglobulin hypermutation and class switch recombination, both AID-dependent mechanisms. SLIP-GC-deficient mice experienced a substantial increase in mutations at G:C base pairs at the region downstream of JH4 in the immunoglobulin heavy chain locus. This change was reflected in the overall mutation frequency, and it was associated with an increase in transitions from G:C base pairs, a hallmark of AID-mediated deamination during replication. In addition, G:C transitions at non-immunoglobulin loci also increased in these mice. Given the intracellular localization of SLIP-GC to sites of replicating DNA, these results suggest that SLIP-GC protects replicating DNA from AID-mediated deamination of cytosines in both strands.
authors: Somatic Hypermutation Group, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors: Kathleen
authors: K
authors: Richter
authors: Lauranell
authors: L
authors: Burch
authors: Frank
authors: F
authors: Chao
authors: David
authors: D
authors: Henke
authors: Chuancang
authors: C
authors: Jiang
authors: Janssen
authors: J
authors: Daly
authors: Ming-Lang
authors: ML
authors: Zhao
authors: Grace
authors: G
authors: Kissling
authors: Marilyn
authors: M
authors: Diaz
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D003596:Cytosine / Q000737:chemistry; D004252:DNA Mutational Analysis; D004261:DNA Replication; D020558:GTP Phosphohydrolases / Q000096:biosynthesis* / Q000235:genetics*; D005838:Genotype; D018858:Germinal Center / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007136:Immunoglobulins / Q000235:genetics*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D010581:Peyer's Patches / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007136:Immunoglobulins; D003596:Cytosine; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D020558:GTP Phosphohydrolases; C576537:SLIP-GC protein, mouse