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Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding.

ABSTRACT: Flap endonuclease 1 (FEN1), a structure-specific endo- and exonuclease, has multiple functions that determine essential biological processes, such as cell proliferation and cell death. As such, the enzyme must be precisely regulated to execute each of its functions with the right timing and in a specific subcellular location. Here we report that FEN1 is methylated at arginine residues, primarily at Arg192. The methylation suppresses FEN1 phosphorylation at Ser187. The methylated form, but not the phosphorylated form, of FEN1 strongly interacts with proliferating cell nuclear antigen (PCNA), ensuring the 'on' and 'off' timing of its reaction. Mutations of FEN1 disrupting arginine methylation and PCNA interaction result in unscheduled phosphorylation and a failure to localize to DNA replication or repair foci. This consequently leads to a defect in Okazaki fragment maturation, a delay in cell cycle progression, impairment of DNA repair and a high frequency of genome-wide mutations.

SUBMITTER: Guo Z

PROVIDER: S-EPMC2943039 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding.

Guo Zhigang Z Zheng Li L Xu Hong H Dai Huifang H Zhou Mian M Pascua Mary Rose MR Chen Qin M QM Shen Binghui B

Nature chemical biology 20100822 10

Flap endonuclease 1 (FEN1), a structure-specific endo- and exonuclease, has multiple functions that determine essential biological processes, such as cell proliferation and cell death. As such, the enzyme must be precisely regulated to execute each of its functions with the right timing and in a specific subcellular location. Here we report that FEN1 is methylated at arginine residues, primarily at Arg192. The methylation suppresses FEN1 phosphorylation at Ser187. The methylated form, but not th ...[more]

PMID: 20729856

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Project description:BackgroundDrug resistance is a major challenge in cancer therapeutics. Abundant evidence indicates that DNA repair systems are enhanced after repetitive chemotherapeutic treatments, rendering cancers cells drug-resistant. Flap endonuclease 1 (FEN1) plays critical roles in DNA replication and repair and in counteracting replication stress, which is a key mechanism for many chemotherapeutic drugs to kill cancer cells. FEN1 was previously shown to be upregulated in response to DNA damaging agents. However, it is unclear about the transcription factors that regulate FEN1 expression in human cancer. More importantly, it is unknown whether up-regulation of FEN1 has an adverse impact on the prognosis of chemotherapeutic treatments of human cancers.MethodsTo reveal regulation mechanism of FEN1 expression, we search and identify FEN1 transcription factors or repressors and investigate their function on FEN1 expression by using a combination of biochemical, molecular, and cellular approaches. Furthermore, to gain insights into the impact of FEN1 levels on the response of human cancer to therapeutic treatments, we determine FEN1 levels in human breast cancer specimens and correlate them to the response to treatments and the survivorship of corresponding breast cancer patients.ResultsWe observe that FEN1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol in breast cancer cells. We identify that the transcription factor/repressor YY1 binds to the FEN1 promoter and suppresses the expression of FEN1 gene. In response to the drug treatments, YY1 is dissociated from the FEN1 promoter region leading over-expression of FEN1. Overexpression of YY1 in the cells results in down-regulation of FEN1 and sensitization of the cancer cells to MMC or taxol. Furthermore, we observe that the level of FEN1 is inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.ConclusionAltogether, our current data indicate that YY1 is a transcription repressor of FEN1 regulating FEN1 levels in response to DNA damaging agents. FEN1 is up-regulated in human breast cancer and its levels inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.

Dataset Information

Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding.

Publications

Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding.

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