scholarly journals A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaau7566 ◽  
Author(s):  
Weizhe Li ◽  
Hong-Yan Wang ◽  
Xiaolu Zhao ◽  
Hongguo Duan ◽  
Binghua Cheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Critical Role ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Damage Repair ◽  
And Function

Polo-like kinase 1 (Plk1) is a crucial regulator of cell cycle progression; but the mechanism of regulation of Plk1 activity is not well understood. We present evidence that Plk1 activity is controlled by a balanced methylation and phosphorylation switch. The methyltransferase G9a monomethylates Plk1 at Lys209, which antagonizes phosphorylation of T210 to inhibit Plk1 activity. We found that the methyl-deficient Plk1 mutant K209A affects DNA replication, whereas the methyl-mimetic Plk1 mutant K209M prolongs metaphase-to-anaphase duration through the inability of sister chromatids separation. We detected accumulation of Plk1 K209me1 when cells were challenged with DNA damage stresses. Ablation of K209me1 delays the timely removal of RPA2 and RAD51 from DNA damage sites, indicating the critical role of K209me1 in guiding the machinery of DNA damage repair. Thus, our study highlights the importance of a methylation-phosphorylation switch of Plk1 in determining its kinase activity and functioning in DNA damage repair.

scholarly journals Human POLD1 modulates cell cycle progression and DNA damage repair

2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Jing Song ◽  
Ping Hong ◽  
Chengeng Liu ◽  
Yueqi Zhang ◽  
Jinling Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Damage Repair

scholarly journals Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

Oncogene ◽  
2005 ◽  
Vol 24 (39) ◽  
pp. 5986-5995 ◽  
Author(s):  
Susan J Marriott ◽  
Oliver John Semmes
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Damage Repair ◽  
Cellular Dna

scholarly journals Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathleen Ho ◽  
Hongwei Luo ◽  
Wei Zhu ◽  
Yi Tang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Genotoxic Stress ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Essential Step

AbstractCHK1 is a crucial DNA damage checkpoint kinase and its activation, which requires ATR and RAD17, leads to inhibition of DNA replication and cell cycle progression. Recently, we reported that SMG7 stabilizes and activates p53 to induce G1 arrest upon DNA damage; here we show that SMG7 plays a critical role in the activation of the ATR-CHK1 axis. Following genotoxic stress, SMG7-null cells exhibit deficient ATR signaling, indicated by the attenuated phosphorylation of CHK1 and RPA32, and importantly, unhindered DNA replication and fork progression. Through its 14-3-3 domain, SMG7 interacts directly with the Ser635-phosphorylated RAD17 and promotes chromatin retention of the 9-1-1 complex by the RAD17-RFC, an essential step to CHK1 activation. Furthermore, through maintenance of CHK1 activity, SMG7 controls G2-M transition and facilitates orderly cell cycle progression during recovery from replication stress. Taken together, our data reveals SMG7 as an indispensable signaling component in the ATR-CHK1 pathway during genotoxic stress response.

scholarly journals FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Shu-Ping Wang ◽  
Shi-Qi Wu ◽  
Shi-Hui Huang ◽  
Yi-Xuan Tang ◽  
Liu-Qiong Meng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Cell Cycle Progression ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Damage Repair

AbstractInducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G2/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.

Development of age-related loss of muscle mass and function – role of oxidative DNA damage repair systems

2021 ◽  
Vol 165 ◽  
pp. 30-31
Author(s):  
Kat Kumiscia ◽  
Shahjahan Shigdar ◽  
Carole Proctor ◽  
Daryl Shanley ◽  
Euan Owen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Muscle Mass ◽  
Oxidative Dna Damage ◽  
Dna Damage Repair ◽  
Age Related ◽  
Damage Repair ◽  
Repair Systems ◽  
And Function

scholarly journals Gcn5p Plays an Important Role in Centromere Kinetochore Function in Budding Yeast

2007 ◽  
Vol 28 (3) ◽  
pp. 988-996 ◽  
Author(s):  
Stefano Vernarecci ◽  
Prisca Ornaghi ◽  
AnaCristina Bâgu ◽  
Enrico Cundari ◽  
Paola Ballario ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Critical Role ◽  
Chromosome Loss ◽  
Cycle Progression ◽  
Kinetochore Assembly ◽  
Spindle Elongation ◽  
And Function ◽  
Insight Into ◽  
Kinetochore Function

ABSTRACT We report that the histone acetyltransferase Gcn5p is involved in cell cycle progression, whereas its absence induces several mitotic defects, including inefficient nuclear division, chromosome loss, delayed G2 progression, and spindle elongation. The fidelity of chromosome segregation is finely regulated by the close interplay between the centromere and the kinetochore, a protein complex hierarchically assembled in the centromeric DNA region, while disruption of GCN5 in mutants of inner components results in sick phenotype. These synthetic interactions involving the ADA complex lay the genetic basis for the critical role of Gcn5p in kinetochore assembly and function. We found that Gcn5p is, in fact, physically linked to the centromere, where it affects the structure of the variant centromeric nucleosome. Our findings offer a key insight into a Gcn5p-dependent epigenetic regulation at centromere/kinetochore in mitosis.

scholarly journals ALR encoding dCMP deaminase is critical for DNA damage repair, cell cycle progression and plant development in rice

2017 ◽  
Vol 68 (21-22) ◽  
pp. 5773-5786 ◽  
Author(s):  
Mei Niu ◽  
Yihua Wang ◽  
Chunming Wang ◽  
Jia Lyu ◽  
Yunlong Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Plant Development ◽  
Cell Cycle Progression ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Damage Repair
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