详细记录  
题名: Excess ribonucleotide reductase R2 subunits coordinate the S phase checkpoint to facilitate DNA damage repair and recovery from replication stress
作者:Z. Ping Lin, Michael F. Belcourt, Rocco Carbone, Jana S. Eaton, Philip G. Penketh, Gerald S. Shadel, Joseph G. Cory and Alan C. Sartorelli
来源:Biochemical Pharmacology[IF=3.617], Volume 73, Issue 6, 15 March 2007, Pages 760-772
URL :http://dx.doi.org/10.1016/j.bcp.2006.11.014
日期:070415
摘要: Z. Ping Lina, Michael F. Belcourtb, Rocco Carbonec, Jana S. Eatond, Philip G. Penketha, Gerald S. Shadele, Joseph G. Coryf and Alan C. Sartorellia, ,

aDepartment of Pharmacology, and Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, United States
bVion Pharmaceuticals, Inc., New Haven, CT, United States cDepartment of Dermatology, and Cancer Center, Yale University School of Medicine, New Haven, CT, United States
dGraduate Program in Genetics and Molecular Biology, Emory University School of Medicine, Atlanta, GA, United States
eDepartment of Pathology, and Cancer Center, Yale University School of Medicine, New Haven, CT, United States
fDepartment of Biochemistry, East Carolina University School of Medicine, Greenville, NC, United States

Received 23 October 2006; accepted 17 November 2006. Available online 23 November 2006.

Summary

Ribonucleotide reductase (RNR), which consists of R1 and R2 subunits, catalyzes a key step of deoxyribonucleoside triphosphate (dNTP) synthesis for DNA replication and repair. The R2 subunit is controlled in a cell cycle-specific manner for timely DNA synthesis and is negatively regulated by p53 in response to DNA damage. Herein we demonstrate that the presence of excess R2 subunits in p53(?/?) HCT-116 human colon cancer cells protects against DNA damage and replication stress. siRNA-mediated stable knockdown (>80%) of excess R2 subunits has no effect on proliferative growth but results in enhanced accumulation of -H2Ax and delayed recovery from DNA lesions inflicted by exposure to cisplatin and Triapine. This accentuated induction of -H2Ax in R2-knockdown cells is attributed to reduced ability to repair damaged DNA and overcome replication blockage. The lack of excess R2 subunits consequently augments chk1 activation and cdc25A degradation, causing impeded cell progression through the S phase and enhanced apoptosis in response to DNA damage and replication stress. In contrast, the level of R1 subunits appears to be limiting, since depletion of the R1 subunit directly activates the S phase checkpoint due to replication stress associated with impaired RNR activity. These findings suggest that excess R2 subunits facilitate DNA damage repair and recovery from replication stress through coordination with the S phase checkpoint in the absence of functional p53. Thus, the level of the R2 subunit constitutes an important determinant of the chemosensitivity of cancer cells and serves as a potential target for enhancement of DNA-damage based therapy. 13.

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