Akt Switches TopBP1 Function from Checkpoint Activation to Transcriptional Regulation through Phosphoserine Binding-Mediated Oligomerization

Liu, Kang; Graves, Joshua D.; Scott, Jessica; Li, Rongbao; Lin, Weei-Chin

doi:10.1128/mcb.00373-13

Cited by 28 publications

(53 citation statements)

References 34 publications

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“…Previously we demonstrate that Akt-mediated phosphorylation of TopBP1 at S1159 regulates its binding to BRCT7/8 domain and oligomerization, leading to a switch of its function from checkpoint activation to transcriptional regulation (28). Because p53 can form tetramers (35), we next tested whether mutp53 bound to TopBP1 and induced its oligomerization in an Aktindependent manner.…”

Section: Mutp53 Inhibits the Checkpoint Function Of Topbp1 By Inducinmentioning

confidence: 99%

“…3F). To rule out a definitive role for Akt, we used an allosteric Akt inhibitor, MK-2206 (28). As shown in Fig.…”

Section: Mutp53 Inhibits the Checkpoint Function Of Topbp1 By Inducinmentioning

confidence: 99%

“…chromatin and ATR binding and inhibits its checkpointactivating functions (28). Hence, Akt switches TopBP1 function from checkpoint activation to transcriptional regulation by regulating TopBP1 quaternary structure.…”

mentioning

confidence: 99%

“…Hence, Akt switches TopBP1 function from checkpoint activation to transcriptional regulation by regulating TopBP1 quaternary structure. In cancer cells harboring high Akt activity, this mechanism is responsible for inhibition of E2F1-dependent apoptosis and ATR function (28).…”

mentioning

confidence: 99%

“…One of them is the regulation of its quaternary structure. Akt phosphorylates TopBP1 at the Ser1159 residue and induces its oligomerization through an intermolecular interaction between the phosphorylated Ser1159 residue (pS1159) and the seventheighth BRCT (BRCT7/8) domains of two individual TopBP1 molecules (23,28). Oligomerization of TopBP1 then induces its binding to E2F1 but at the same time prevents its recruitment to Significance Mutant form of p53 (mutp53) proteins are expressed at high levels in many human cancers and can promote tumor cell growth.…”

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confidence: 99%

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Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Liu

Lin

Graves

et al. 2017

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

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Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress. The effect on ATR response caused by mutp53 can be exploited in a synthetic lethality strategy, as depletion of another ATR activator, DNA2, in mutp53-R273H-expressing cancer cells renders cells hypersensitive to cisplatin. Expression of mutp53-R273H also makes cancer cells more sensitive to DNA2 depletion or DNA2 inhibitors. In addition to ATR-activating function during replication stress, TopBP1 interacts with Treslin in a Cdk-dependent manner to initiate DNA replication during normal growth. We find that mutp53 also interferes with TopBP1 replication function. Several contact, but not conformational, mutp53s enhance the interaction between TopBP1 and Treslin and promote DNA replication despite the presence of a Cdk2 inhibitor. Together, these data uncover two distinct mechanisms by which mutp53 enhances DNA replication: (i) Both contact and conformational mutp53s can bind TopBP1 and attenuate the checkpoint response to replication stress, and (ii) during normal growth, contact (but not conformational) mutp53s can override the Cdk2 requirement to promote replication by facilitating the TopBP1/Treslin interaction.ormal cells use various fundamental braking mechanisms to properly respond to environmental cues and coordinate the execution of different phases of cell cycle. Tumor suppressors p53 and pRb are the key regulators for G1 checkpoint, which are frequently lost in many types of cancer (1). Mutations of TP53 are found in half of all human cancers, including nearly all smallcell lung cancers, squamous cell lung cancers, high-grade serous ovarian cancer (2-4), and greater than 80% of glioblastoma and basal-like breast cancer (5, 6). Therefore, understanding the contribution of TP53 mutations in carcinogenesis is very important for the development of new strategies to prevent cancer progression and improve the efficacy of cancer therapy.In addition to the loss of normal p53 function, mutant form of p53 (mutp53) proteins acquire new oncogenic properties (gainof-function, GOF), such as promoting cancer cell proliferation, metastasis, genomic instability, resistance to chemotherapy, etc. (7-9). Among the many mechanisms of mutp53 GOF, the checkpoint activator TopBP1 (topoisomerase IIβ-binding protein) has been identified as a critical mediator for facilitating complex formation between several hotspot mutp53 proteins and either NF-Y or p63/p73 (10). TopBP1 interacts with these mutp53s and NF-Y and promotes mutp53 and p300 recruitment to N...

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Section: Mutp53 Inhibits the Checkpoint Function Of Topbp1 By Inducinmentioning

confidence: 99%

“…3F). To rule out a definitive role for Akt, we used an allosteric Akt inhibitor, MK-2206 (28). As shown in Fig.…”

Section: Mutp53 Inhibits the Checkpoint Function Of Topbp1 By Inducinmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Liu

Lin

Graves

et al. 2017

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

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A novel function of hepatocyte growth factor in the activation of checkpoint kinase 1 phosphorylation in colon cancer cells

Song

Che

et al. 2017

Mol Cell Biochem

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The ATR/checkpoint kinase 1 (Chk1) pathway plays an essential role in modulating the DNA damage response and homologous recombination. Particularly, Chk1 phosphorylation is related to cancer prognosis and therapeutic resistance. Some receptor tyrosine kinases participate in the regulation of Chk1 phosphorylation; however, the effect of hepatocyte growth factor (HGF) on Chk1 phosphorylation is unknown. In the present study, we demonstrated that HGF moderately activated Chk1 phosphorylation in colon cancer cells by upregulating TopBP1 and RAD51, and promoting TopBP1–ATR complex formation. Furthermore, AKT activity, which was promoted by HGF, served as an important mediator linking HGF/MET signaling and Chk1 phosphorylation. Depleting AKT activity attenuated basal expression of p-Chk1 and HGF-induced Chk1 activation. Moreover, AKT activity directly regulated TopBP1 and RAD51 expression. AKT inhibition suppressed HGF-induced upregulation of TopBP1 and RAD51, and enhanced TopBP1/ATR complex formation. Our results show that HGF was involved in regulating Chk1 phosphorylation, and further demonstrate that AKT activity was responsible for this HGF-induced Chk1 phosphorylation. These findings might potentially result in management of prognosis and therapeutic sensitivity in cancer therapy.

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TopBP1: A BRCT-scaffold protein functioning in multiple cellular pathways

2014

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Akt Switches TopBP1 Function from Checkpoint Activation to Transcriptional Regulation through Phosphoserine Binding-Mediated Oligomerization

Cited by 28 publications

References 34 publications

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

A novel function of hepatocyte growth factor in the activation of checkpoint kinase 1 phosphorylation in colon cancer cells

TopBP1: A BRCT-scaffold protein functioning in multiple cellular pathways

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