SIRT1 regulates the function of the Nijmegen breakage syndrome protein.
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.
Yuan
Zhigang
Z
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Zhang
Xiaohong
X
Sengupta
Nilanjan
N
Lane
William S
WS
Seto
Edward
E
D000107:Acetylation / Q000528:radiation effects; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000528:radiation effects; D004247:DNA / Q000096:biosynthesis; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000528:radiation effects; D011839:Radiation, Ionizing; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D010768:Phosphoserine; D004247:DNA; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases