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SIRT2 Directs the Replication Stress Response Through CDK9 Deacetylation

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SIRT2 Directs the Replication Stress Response Through CDK9 Deacetylation SIRT2 directs the replication stress response through CDK9 deacetylation Hui Zhanga,1, Seong-Hoon Parkb,1, Brooke G. Pantazidesa, Oleksandra Karpiukc, Matthew D. Warrena,ClaireW.Hardya, Duc M. Duongd, So-Jeong Park e, Hyun-Seok Kim e, Athanassios Vassilopoulos b,NicholasT.Seyfriedd,StevenA.Johnsenc, David Giusb,andDavidS.Yua,2 aDepartment of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322; bDepartment of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; cDepartment of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; dDepartment of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322; and eDepartment of Life Science, College of Natural Science, Ewha Womans University, Seoul 120-750, Korea Edited by Kevin Struhl, Harvard Medical School, Boston, MA, and approved July 1, 2013 (received for review January 23, 2013) Sirtuin 2 (SIRT2) is a sirtuin family deacetylase that directs acety- instability, and expression of fragile sites of mammalian chro- lome signaling, protects genome integrity, and is a murine tumor mosomes (22). ATR senses stalled replication forks that result suppressor. We show that SIRT2 directs replication stress re- from uncoupling that exposes replication protein A (RPA)- sponses by regulating the activity of cyclin-dependent kinase 9 bound single-stranded DNA (ssDNA) (23). Finally, RSR mobi- (CDK9), a protein required for recovery from replication arrest. lizes several activities necessary to maintain genome integrity, SIRT2 deficiency results in replication stress sensitivity, impairment including arresting the cell cycle, inhibiting the onset of mitosis, in recovery from replication arrest, spontaneous accumulation of stabilizing the stalled replication fork, and facilitating repli- replication protein A to foci and chromatin, and a G2/M checkpoint cation recovery. deficit. SIRT2 interacts with and deacetylates CDK9 at lysine 48 in Although cyclin-dependent kinase 9 (CDK9) is a well-char- response to replication stress in a manner that is partially depen- acterized component of the positive transcription elongation fac- dent on ataxia telangiectasia and Rad3 related (ATR) but not cyclin tor b complex with cyclin T or K (24, 25), it also has a direct role T or K, thereby stimulating CDK9 kinase activity and promoting in promoting RSR activities, which is functionally conserved in yeast (26–29). Loss of CDK9 activity increases spontaneous recovery from replication arrest. Moreover, wild-type, but not levels of DNA damage signaling in replicating cells and a de- acetylated CDK9, alleviates the replication stress response impair- creased ability to recover from a transient replication arrest. ment of SIRT2 deficiency. Collectively, our results define a function CDK9 localizes to chromatin to limit the amount of ssDNA after for SIRT2 in regulating checkpoint pathways that respond to rep- replication stress and interacts in a complex with ATR as well as lication stress through deacetylation of CDK9, providing insight other checkpoint signaling proteins. CDK9 also phosphorylates into how SIRT2 maintains genome integrity and a unique mecha- and activates ubiquitin-conjugating enzyme 2A (UBE2A) (30– nism by which SIRT2 may function, at least in part, as a tumor 32), which directs H2B and PCNA ubiquitination (33, 34). The suppressor protein. role for CDK9 in the RSR is independent of cyclin T (29), and we and others have shown that cyclin K also functions to main- DNA damage | cell cycle checkpoint | genome maintenance tain genome integrity (29, 35); however, recent evidence suggests that cyclin K functions primarily with CDK12 (35–37). Similar to + embers of the sirtuin NAD -dependent deacetylase family other RSR proteins, CDK9 activity is regulated by posttrans- Mregulate multiple biological processes, including genome lational modification, including acetylation (38). CDK9 is acet- maintenance, aging, tumorigenesis, differentiation, and metab- ylated on lysine 44 by the p300 acetyltransferase (39), which olism (1–3). There are seven mammalian homologs of yeast si- promotes its activity, and lysine 48 by the general control non- lent information regulator 2 (Sir2). Whereas sirtuin 1 (SIRT1) depressible 5 (GCN5) and P300/CBP-associated factor (P/CAF) and sirtuin 6 (SIRT6) have been linked directly to DNA repair or acetyltransferases (40), which inhibits its activity. Lysine 44 of DNA damage response (DDR) signaling pathways (4–12), the CDK9 is also deacetylated by histone deacetylase 3 (HDAC3) role for other sirtuin family members, including SIRT2, is less and histone deacetylase 1 (HDAC1) (39); however, the deace- clear. Mice deficient in Sirt2 develop breast, liver, and other tylase for lysine 48 of CDK9 is not known. It is also not known cancers (13, 14), and SIRT2 expression is decreased in human whether the acetylation status or kinase activity of CDK9 is breast and liver cancers (14), suggesting that SIRT2 is a tumor regulated by DNA damage. In this study, we show that SIRT2, suppressor protein (TSP). In support of a role for SIRT2 in the and by extension the cellular acetylome, has a role in promoting DDR, Sirt2 deficiency in mouse embryo fibroblasts (MEFs) replication stress response activities by regulating CDK9 activity results in a mitotic checkpoint deficit, increased DNA damage, via changes in lysine acetylation. and genomic instability (13). In addition, SIRT2 deficiency in chicken DT40 cells induces hypersensitivity to cisplatin (15). Results SIRT2 also deacetylates histone H3 lysine 56, a marker for Silencing SIRT2 Causes Sensitivity to Replication Stress. To inves- packaging of newly replicated and repaired DNA into chromatin tigate the role of SIRT2 in mediating recovery following replication (16), implying that SIRT2 may function in the maintenance of genome integrity during DNA replication. The replication stress response (RSR) is a subset of the DDR Author contributions: H.Z., S.-H.P., B.G.P., O.K., C.W.H., D.M.D., S.-J.P., H.-S.K., A.V., N.T.S., signaling network that recognizes challenges to DNA replication S.A.J., D.G., and D.S.Y. designed research; H.Z., S.-H.P., B.G.P., O.K., M.D.W., C.W.H., D.M.D., and mobilizes diverse DNA repair and cell cycle checkpoint S.-J.P., H.-S.K., A.V., N.T.S., and D.S.Y. performed research; H.Z., S.-H.P., B.G.P., O.K., M.D.W., pathways. The RSR is critical for the prevention of cancer by C.W.H., D.M.D., S.-J.P., H.-S.K., A.V., N.T.S., S.A.J., D.G., and D.S.Y. analyzed data; and H.Z. and D.S.Y. wrote the paper. acting as a barrier against genomic instability and tumorigenesis (17, 18). At the apex of the RSR signaling cascade is the ataxia- The authors declare no conflict of interest. telangiectasia and Rad3-related protein (ATR) checkpoint This article is a PNAS Direct Submission. kinase (19). ATR function is essential to stabilize stalled rep- 1H.Z. and S.-H.P. contributed equally to this work. lication forks and promote recovery. Disruption of ATR causes 2To whom correspondence should be addressed. E-mail: [email protected]. early embryonic lethality in mice (20), and cells lacking ATR have This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. defects associated with DNA replication (21), chromosomal 1073/pnas.1301463110/-/DCSupplemental. 13546–13551 | PNAS | August 13, 2013 | vol. 110 | no. 33 www.pnas.org/cgi/doi/10.1073/pnas.1301463110 Downloaded by guest on September 29, 2021 fork arrest, we measured the ability of U2OS human osteosar- analysis confirmed expression of the exogenously expressed fu- coma cells, silenced for SIRT2, to recover from a transient high sion proteins and efficiency of SIRT2 silencing (Fig. 1F). As a dose hydroxyurea (HU) exposure, a drug that stalls DNA rep- second measure for determining the significance of SIRT2 lication forks by inhibiting ribonucleotide reductase. U2OS cells deacetylase activity in the RSR, we generated mouse mammary were treated with or without HU for 24 h, allowed to recover for tumor Sirt2 knockout (MMT S2KO) cell lines (14), stably expressing 24 h, and assayed for cell viability using water soluble tetrazolium SIRT2 WT or SIRT2 H187Y (Fig. 1H) and assessed colony salt (WST)-1 reagent. siRNA knockdown of ATR or ATR- formation following a 24-h pulse of HU. SIRT2 WT but not interacting protein (ATRIP) caused HU hypersensitivity, com- SIRT2 H187Y significantly increased the percentage of surviving pared with nontargeting (NT) controls as has been previously colonies following HU treatment in a dose-dependent manner shown (30) (Fig. 1 A and E). Similarly, SIRT2 knockdown re- (Fig. 1G), confirming that the deacetylase activity of SIRT2 is sulted in HU hypersensitivity (Fig. 1 A and E). Western blot required for the RSR. analysis confirmed decreased levels of SIRT2 following siRNA knockdown (Fig. 1 B and F). The HU hypersensitivity of cells SIRT2 Is a Replication Stress Response Protein. The ability of SIRT2- after SIRT2 knockdown was observed between 24 and 72 h silenced cells to recover from transient replication fork arrest was following recovery from the HU challenge (Fig. S1A). SIRT2 assessed using cell cycle recovery by flow cytometry. Eight to 10 h silencing also caused hypersensitivity to gemcitabine, cisplatin, after removing HU, U2OS, telomerase immortalized human retinal and mitomycin C (Fig. S1 B–D), implying that SIRT2 responds pigment epithelium (hTERT RPE-1), and human colorectal carci- generally to replication stress. noma cell line HCT-116 cells treated with NT siRNA progressed As SIRT2 can affect the production of NADH, which is measured through S phase and accumulated 4N DNA content, whereas cells by WST-1 reagent, we also determined HU sensitivity of SIRT2- treated with ATR, ATRIP or SIRT2 siRNA exhibited delayed depleted cells using a colony formation assay. U2OS cells stably S-phase progression (Fig. 2 A and B and Fig. S2 A–D).
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