Journal ArticleDOI
Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
TLDR
The molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed and apoptosis, which eliminates heavily damaged or seriously deregulated cells, is analyzed.Abstract:
DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.read more
Citations
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Journal ArticleDOI
Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
Shideng Bao,Qiulian Wu,Roger E. McLendon,Yueling Hao,Qing Ming Shi,Anita B. Hjelmeland,Mark W. Dewhirst,Darell D. Bigner,Jeremy N. Rich +8 more
TL;DR: This work shows that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity, and suggests that CD133-positive tumour cells could be the source of tumour recurrence after radiation.
Journal ArticleDOI
Molecular mechanisms of cisplatin resistance
Lorenzo Galluzzi,Laura Senovilla,Laura Senovilla,Laura Senovilla,Ilio Vitale,Ilio Vitale,Ilio Vitale,Judith Michels,Judith Michels,Judith Michels,Isabelle Martins,Isabelle Martins,Isabelle Martins,Oliver Kepp,Oliver Kepp,Oliver Kepp,Maria Castedo,Maria Castedo,Maria Castedo,Guido Kroemer +19 more
TL;DR: A systematic discussion of the mechanisms that account for the cisplatin-resistant phenotype of tumor cells are described and the development of chemosensitization strategies constitute a goal with important clinical implications.
Journal ArticleDOI
PCNA, the Maestro of the Replication Fork
TL;DR: Proliferating cell nuclear antigen -a cofactor of DNA polymerases that encircles DNA-orchestrates several of these functions by recruiting crucial players to the replication fork, indicating that these interactions do not occur simultaneously during replication.
Journal ArticleDOI
Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Raul Mostoslavsky,Katrin F. Chua,Katrin F. Chua,David B. Lombard,Wendy W. Pang,Miriam R. Fischer,Lionel Gellon,Pingfang Liu,Gustavo Mostoslavsky,Sonia Franco,Michael M. Murphy,Kevin D. Mills,Parin Patel,Joyce T. Hsu,Andrew L. Hong,Ethan Ford,Hwei Ling Cheng,Caitlin Kennedy,Nomeli P. Nunez,Nomeli P. Nunez,Roderick T. Bronson,David Frendewey,Wojtek Auerbach,David M. Valenzuela,Margaret Karow,Michael O. Hottiger,Stephen D. Hursting,J. Carl Barrett,J. Carl Barrett,Leonard Guarente,Richard C. Mulligan,Bruce Demple,George D. Yancopoulos,Frederick W. Alt +33 more
TL;DR: It is demonstrated that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER).
Journal ArticleDOI
The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor
TL;DR: The DNA damage response, previously shown to arrest the cell cycle and enhance DNA repair functions, or to trigger apoptosis, may also participate in alerting the immune system to the presence of potentially dangerous cells.
References
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Journal ArticleDOI
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases
TL;DR: In this article, an improved two-hybrid system was employed to isolate human genes encoding Cdk-interacting proteins (Cips) and found that CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2.
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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
TL;DR: It is shown that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain.
Journal ArticleDOI
The DNA damage response: putting checkpoints in perspective
TL;DR: The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumour development, and this work has shown that direct activation of DNA repair networks is needed to correct this problem.
Journal ArticleDOI
A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia
Michael B. Kastan,Qimin Zhan,Wafik S. El-Deiry,Tyler Jacks,William V. Walsh,Beverly Plunkett,Bert Vogelstein,Albert J. Fornace +7 more
TL;DR: Three participants are identified (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.
Journal ArticleDOI
Checkpoints: controls that ensure the order of cell cycle events
Leland H. Hartwell,Ted Weinert +1 more
TL;DR: It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.