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PMID:17612497

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Citation

Yuan, Z, Zhang, X, Sengupta, N, Lane, WS and Seto, E (2007) SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol. Cell 27:149-62

Abstract

MRE11-RAD50-NBS1 (MRN) is a conserved nuclease complex that exhibits properties of a DNA damage sensor and is critical in regulating cellular responses to DNA double-strand breaks. NBS1, which is mutated in the human genetic disease Nijmegen breakage syndrome, serves as the regulatory subunit of MRN. Phosphorylation of NBS1 by the ATM kinase is necessary for both activation of the S phase checkpoint and for efficient DNA damage repair response. Here, we report that NBS1 is an acetylated protein and that the acetylation level is tightly regulated by the SIRT1 deacetylase. SIRT1 associates with the MRN complex and, importantly, maintains NBS1 in a hypoacetylated state, which is required for ionizing radiation-induced NBS1 Ser343 phosphorylation. Our results demonstrate the presence of crosstalk between two different posttranslational modifications in NBS1 and strongly suggest that deacetylation of NBS1 by SIRT1 plays a key role in the dynamic regulation of the DNA damage response and in the maintenance of genomic stability.

Links

PubMed PMC2679807 Online version:10.1016/j.molcel.2007.05.029

Keywords

Acetylation/radiation effects; Animals; Cell Cycle Proteins/metabolism; Cell Survival/radiation effects; DNA/biosynthesis; HeLa Cells; Histone Deacetylases/metabolism; Humans; Mice; Nuclear Proteins/metabolism; Phosphorylation/radiation effects; Phosphoserine/metabolism; Protein Binding/radiation effects; Radiation, Ionizing; Sirtuin 1; Sirtuins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NBN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49959

F

Seeded From UniProt

complete

HUMAN:NBN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96EB6

F

Seeded From UniProt

complete

HUMAN:MRE11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60934

F

Seeded From UniProt

complete

HUMAN:SIR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60934

F

Seeded From UniProt

complete

HUMAN:SIRT1

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIRT1

involved_in

GO:0071479: cellular response to ionizing radiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIRT1

involved_in

GO:0000731: DNA synthesis involved in DNA repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIRT1

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIR1

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIR1

involved_in

GO:0000731: DNA synthesis involved in DNA repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIR1

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIR1

involved_in

GO:0071479: cellular response to ionizing radiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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