A role for PCNA ubiquitination in immunoglobulin hypermutation.
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 PCNA(K164R) 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.
Arakawa
Hiroshi
H
Gesellschaft für Strahlen Forschung, Institute for Molecular Radiobiology, Neuherberg-Munich, Germany.
Moldovan
George-Lucian
GL
Saribasak
Huseyin
H
Saribasak
Nesibe Nur
NN
Jentsch
Stefan
S
Buerstedde
Jean-Marie
JM
D000818:Animals; D001483:Base Sequence; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D004249:DNA Damage; D006801:Humans; D007146:Immunoglobulin lambda-Chains / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics* / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes
D007146:Immunoglobulin lambda-Chains; D009153:Mutagens; D018809:Proliferating Cell Nuclear Antigen; D025841:Small Ubiquitin-Related Modifier Proteins; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes