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SUMOylation of PCNA by PIAS1 and PIAS4 promotes template switch in the chicken and human B cell lines
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SUMOylation of PCNA by PIAS1 and PIAS4 promotes template switch in the chicken and human B cell lines
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Journal Article
SUMOylation of PCNA by PIAS1 and PIAS4 promotes template switch in the chicken and human B cell lines
2018
Overview
DNA damage tolerance (DDT) releases replication blockage caused by damaged nucleotides on template strands employing two alternative pathways, error-prone translesion DNA synthesis (TLS) and error-free template switch (TS). Lys164 of proliferating cell nuclear antigen (PCNA) is SUMOylated during the physiological cell cycle. To explore the role for SUMOylation of PCNA in DDT, we characterized chicken DT40 and human TK6 B cells deficient in the PIAS1 and PIAS4 small ubiquitin-like modifier (SUMO) E3 ligases. DT40 cells have a unique advantage in the phenotypic analysis of DDT as they continuously diversify their immunoglobulin (Ig) variable genes by TLS and TS [Ig gene conversion (GC)], both relieving replication blocks at abasic sites without accompanying by DNA breakage. Remarkably, PIAS1
−/−/PIAS4
−/− cells displayed amultifold decrease in SUMOylation of PCNA at Lys164 and over a 90% decrease in the rate of TS. Likewise, PIAS1
−/−/PIAS4
−/− TK6 cells showed a shift of DDT from TS to TLS at a chemosynthetic UV lesion inserted into the genomic DNA. The PCNA
K164R/K164R
mutation caused a ∼90% decrease in the rate of Ig GC and no additional impact on PIAS1
−/−/PIAS4
−/− cells. This epistatic relationship between the PCNA
K164R/K164R
and the PIAS1
−/−/PIAS4
−/− mutations suggests that PIAS1 and PIAS4 promote TS mainly through SUMOylation of PCNA at Lys164. This idea is further supported by the data that overexpression of a PCNA-SUMO1 chimeric protein restores defects in TS in PIAS1
−/−/PIAS4
−/− cells. In conclusion, SUMOylation of PCNA at Lys164 promoted by PIAS1 and PIAS4 ensures the error-free release of replication blockage during physiological DNA replication in metazoan cells.
Publisher
National Academy of Sciences
Subject
/ Breakage
/ Cells
/ Chickens
/ DNA
/ Errors
/ Genes
/ Genes, Immunoglobulin - genetics
/ Genetics
/ Humans
/ Immunoglobulin Variable Region - genetics
/ Mutation
/ Poly-ADP-Ribose Binding Proteins - genetics
/ Proliferating cell nuclear antigen
/ Proliferating Cell Nuclear Antigen - genetics
/ Protein Inhibitors of Activated STAT - genetics
/ Proteins
