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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #295408

Title: The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation

item SERRANO, LOURDES - Rutgers University
item MARTINEZ-REDONDO, PALOMO - Institut D’Investigacio Biomedica De Bellvitge (IDIBELL)
item MARAZUELA-DUQUE, ANNA - Institut D’Investigacio Biomedica De Bellvitge (IDIBELL)
item VASQUEZ, BERTA - Rutgers University
item DOOLEY, SCOTT - Rutgers University
item VOIGT, PHILLIP - New York University School Of Medicine
item BECK, DAVID - New York University School Of Medicine
item KANE-GOLDSMITH, NORIKO - Rutgers University
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)
item RABANAL, ROSA - University Of Barcelona
item FONDEVILA, DOLORS - University Of Barcelona
item MUNOZ, PURIFICACION - Institut D’Investigacio Biomedica De Bellvitge (IDIBELL)
item KRUGER, MARCUS - Desiderio Finamore Veterinary Research Institute (FEPAGRO)
item TISCHFIELD, JAY - Rutgers University
item VAQUERO, ALEJANDRO - Institut D’Investigacio Biomedica De Bellvitge (IDIBELL)

Submitted to: Genes and Development
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/11/2013
Publication Date: 4/9/2013
Citation: Serrano, L., Martinez-Redondo, P., Marazuela-Duque, A., Vasquez, B.N., Dooley, S.J., Voigt, P., Beck, D.B., Kane-Goldsmith, N., Tong, Q., Rabanal, R.M., Fondevila, D., Munoz, P., Kruger, M. 2013. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes and Development. 27(6):639-653.

Interpretive Summary: The SIRT2 protein belongs to a family of enzymes called sirtuins that can bind and modify (deacetylate) other proteins. Sirtuin proteins regulate many aspects of cellular functions, including cell growth, cell death, stress response, metabolism and aging. In this study, we find that SIRT2 binds to another protein called PR-Set7 during cell proliferation or cell stress. This action causes PR-Set7 to bind better to chromatin, the DNA-containing genetic material within a cell. PR-Set7 modifies the chromatin structure proteins (histones) that are associated with DNA to maintain the integrity of chromatin. In mice lacking of SIRT2, the chromatin integrity is prone to be breached, resulting in genetic mutations that cause tumor formation. This study reveals a role of SIRT2 in the maintenance of chromatin stability and prevention of tumor formation.

Technical Abstract: The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1–3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.