title: DNA damage invokes mismatch repair-dependent cyclin D1 attenuation and retinoblastoma signaling pathways to inhibit CDK2.
abstract: DNA-damage evokes cell cycle checkpoints, which function to maintain genomic integrity. The retinoblastoma tumor suppressor (RB) and mismatch repair complexes are known to contribute to the appropriate cellular response to specific types of DNA damage. However, the signaling pathways through which these proteins impact the cell cycle machinery have not been explicitly determined. RB-deficient murine embryo fibroblasts continued a high degree of DNA replication following the induction of cisplatin damage, but were inhibited for G(2)/M progression. This damage led to RB dephosphorylation/activation and subsequent RB-dependent attenuation of cyclin A and CDK2 activity. In both Rb+/+ and Rb -/- cells, cyclin D1 expression was attenuated following DNA damage. As cyclin D1 is a critical determinant of RB phosphorylation and cell cycle progression, we probed the pathway through which cyclin D1 degradation occurs in response to DNA damage. We found that attenuation of endogenous cyclin D1 is dependent on multiple mismatch repair proteins. We demonstrate that the mismatch repair-dependent attenuation of endogenous cyclin D1 is critical for attenuation of CDK2 activity and induction of cell cycle checkpoints. Together, these studies couple the activity of the retinoblastoma and mismatch repair tumor suppressor pathways through the degradation of cyclin D1 and dual attenuation of CDK2 activity.
authors.affiliation: Department of Cell Biology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors.forename: Zhengdao
authors.initials: Z
authors.lastname: Lan
authors.forename: Zvjezdana
authors.initials: Z
authors.lastname: Sever-Chroneos
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Strobeck
authors.forename: Chi-Hyun
authors.initials: CH
authors.lastname: Park
authors.forename: R
authors.initials: R
authors.lastname: Baskaran
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D020137:Base Pair Mismatch; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D016195:G2 Phase; D015151:Immunoblotting; D051379:Mice; D008856:Microscopy, Fluorescence; D008938:Mitosis; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D019925:Cyclin A; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin