a role for pcna ubiquitination in immunoglobulin hypermutation增殖细胞核抗原在免疫球蛋白hypermutation泛素化作用.pdfVIP

PLoS BIOLOGY A Role for PCNA Ubiquitination in Immunoglobulin Hypermutation 1 2 1 1 2 Hiroshi Arakawa , George-Lucian Moldovan , Huseyin Saribasak , Nesibe Nur Saribasak , Stefan Jentsch , 1* Jean-Marie Buerstedde ¨ 1 Gesellschaft fur Strahlen Forschung, Institute for Molecular Radiobiology, Neuherberg-Munich, Germany, 2 Max Planck Institute of Biochemistry, Department of Molecular Cell Biology, Martinsried-Munich, Germany Proliferating cell nuclear antigen (PCNA) is a DNA polymerase cofactor and regulator of replication-linked functions. Upon DNA damage, yeast and vertebrate PCNA is modified at the conserved lysine K164 by ubiquitin, which mediates error-prone replication across lesions via translesion polymerases. We investigated the role of PCNA ubiquitination in variants of the DT40 B cell line that are mutant in K164 of PCNA or in Rad18, which is involved in PCNA ubiquitination. Remarkably, the PCNAK164R mutation not only renders cells sensitive to DNA-damaging agents, but also strongly reduces activation induced deaminase-dependent single-nucleotide substitutions in the immunoglobulin light-chain locus. This is the first evidence, to our knowledge, that vertebrates exploit the PCNA-ubiquitin pathway for immunoglobulin hypermutation, most likely through the recruitment of error-prone DNA polymerases. Citation: Arakawa H, Moldovan GL, Saribasak H, Saribasak NN, Jentsch S, et al. (2006) A role for PCNA ubiquitination in immunoglobulin hypermutation. PLoS Biol 4(11): e366. DOI: 10.1371/journal.pbio.0040366 Introduction