A role for CDK9 in UV damage response

Morawska, Magdalena

doi:10.4161/cc.20963

Cited by 1 publication

(2 citation statements)

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“…U2OS cells were treated with or without HU for 24 h, allowed to recover for 24 h, and assayed for cell viability using water soluble tetrazolium salt (WST)-1 reagent. siRNA knockdown of ATR or ATRinteracting protein (ATRIP) caused HU hypersensitivity, compared with nontargeting (NT) controls as has been previously shown (30) (Fig. 1 A and E).…”

Section: Resultsmentioning

confidence: 80%

“…CDK9 localizes to chromatin to limit the amount of ssDNA after replication stress and interacts in a complex with ATR as well as other checkpoint signaling proteins. CDK9 also phosphorylates and activates ubiquitin-conjugating enzyme 2A (UBE2A) (30)(31)(32), which directs H2B and PCNA ubiquitination (33,34). The role for CDK9 in the RSR is independent of cyclin T (29), and we and others have shown that cyclin K also functions to maintain genome integrity (29,35); however, recent evidence suggests that cyclin K functions primarily with CDK12 (35)(36)(37).…”

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confidence: 99%

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SIRT2 directs the replication stress response through CDK9 deacetylation

Zhang

Park

Pantazides

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Sirtuin 2 (SIRT2) is a sirtuin family deacetylase that directs acetylome signaling, protects genome integrity, and is a murine tumor suppressor. We show that SIRT2 directs replication stress responses by regulating the activity of cyclin-dependent kinase 9 (CDK9), a protein required for recovery from replication arrest. SIRT2 deficiency results in replication stress sensitivity, impairment in recovery from replication arrest, spontaneous accumulation of replication protein A to foci and chromatin, and a G2/M checkpoint deficit. SIRT2 interacts with and deacetylates CDK9 at lysine 48 in response to replication stress in a manner that is partially dependent on ataxia telangiectasia and Rad3 related (ATR) but not cyclin T or K, thereby stimulating CDK9 kinase activity and promoting recovery from replication arrest. Moreover, wild-type, but not acetylated CDK9, alleviates the replication stress response impairment of SIRT2 deficiency. Collectively, our results define a function for SIRT2 in regulating checkpoint pathways that respond to replication stress through deacetylation of CDK9, providing insight into how SIRT2 maintains genome integrity and a unique mechanism by which SIRT2 may function, at least in part, as a tumor suppressor protein.DNA damage | cell cycle checkpoint | genome maintenance M embers of the sirtuin NAD + -dependent deacetylase family regulate multiple biological processes, including genome maintenance, aging, tumorigenesis, differentiation, and metabolism (1-3). There are seven mammalian homologs of yeast silent information regulator 2 (Sir2). Whereas sirtuin 1 (SIRT1) and sirtuin 6 (SIRT6) have been linked directly to DNA repair or DNA damage response (DDR) signaling pathways (4-12), the role for other sirtuin family members, including SIRT2, is less clear. Mice deficient in Sirt2 develop breast, liver, and other cancers (13,14), and SIRT2 expression is decreased in human breast and liver cancers (14), suggesting that SIRT2 is a tumor suppressor protein (TSP). In support of a role for SIRT2 in the DDR, Sirt2 deficiency in mouse embryo fibroblasts (MEFs) results in a mitotic checkpoint deficit, increased DNA damage, and genomic instability (13). In addition, SIRT2 deficiency in chicken DT40 cells induces hypersensitivity to cisplatin (15). SIRT2 also deacetylates histone H3 lysine 56, a marker for packaging of newly replicated and repaired DNA into chromatin (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 signaling network that recognizes challenges to DNA replication and mobilizes diverse DNA repair and cell cycle checkpoint pathways. The RSR is critical for the prevention of cancer by acting as a barrier against genomic instability and tumorigenesis (17,18). At the apex of the RSR signaling cascade is the ataxiatelangiectasia and Rad3-related protein (ATR) checkpoint kinase (19). ATR function is essential to stabilize stalled replication forks and promote recovery. Disruption of ...

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Section: Resultsmentioning

confidence: 80%