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Functional Analysis of the Role of Phosphorylated PCNA in Cancer Development and its Potential in Cancer Therapy
Author(s) -
Peng Bo,
Jiang Qingwen,
Ortega Janice,
Gu Liya,
Dai Junbiao,
Li GuoMin
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.906.2
Subject(s) - proliferating cell nuclear antigen , phosphorylation , dna replication , dna mismatch repair , dna repair , biology , sumo protein , microbiology and biotechnology , cancer research , ubiquitin , dna , biochemistry , gene
Proliferating cell nuclear antigen (PCNA), a ring‐shaped homotrimer, is an essential factor in DNA metabolism including DNA replication and repair. PCNA functions in these reactions appear to be regulated by posttranslational modifications, such as ubiquitylation, sumoylation and phosphorylation . Recently, we have shown that PCNA phosphorylation by EGFR at tyrosine 211 (Y211) disrupts PCNA interactions with mismatch recognition proteins, thereby inhibiting DNA mismatch repair (MMR). In addition, phosphorylated PCNA promotes misincorporation during DNA replication. However, it is unknown whether one, two or all three phosphorylated subunits are responsible for MMR inhibition and error‐prone DNA synthesis. To answer this question, we created a series of phosphorylation‐mimicking and non‐phosphorylation‐mimicking PCNA molecules with variously phosphorylated subunits, and examined their roles in MMR and DNA synthesis in vitro and in vivo . Our biochemical experiments reveal that all forms of phosphorylated PCNA inhibit MMR, with the inhibition activity proportional to the increased levels of phosphorylation; all forms of phosphorylated PCNA slow down the speed of DNA synthesis while conducting error‐prone DNA synthesis. Our in vivo data show that high‐levels of PCNA phosphorylation induce cell death. This study therefore provides novel mechanisms for phosphorylated PCNA in cancer development and its potential role in cancer therapy. Support or Funding Information This work is supported in part by grants from National Natural Science Foundation of China (31370766), by Tsinghua‐Peking Joint Center for Life Sciences, and by National Institutes of Health of the United States (GM089684).