title: Structure meets function--centrosomes, genome maintenance and the DNA damage response.
abstract: Centrosomes are cytoplasmic organelles playing a fundamental role in organizing both the interphase cytoskeleton and the bipolar mitotic spindle. In addition, the centrosome has recently come into focus as part of the network that integrates cell cycle arrest and repair signals in response to genotoxic stress--the DNA damage response. One important mediator of this response, the checkpoint kinase Chk1, has been shown to negatively regulate the G(2)/M transition via its centrosomal localization. Moreover, there is growing evidence that a centrosome inactivation checkpoint exists, which utilizes DNA damage-induced centrosome fragmentation or amplification to provoke a "mitotic catastrophe" and eliminate damaged cells. Candidate regulators of this centrosomal checkpoint include the checkpoint kinase Chk2 and its upstream regulators ATM and ATR. In addition, a growing number of other proteins have been implicated in centrosomal regulation of the DNA damage response, e.g. the tumor suppressor p53, the breast cancer susceptibility gene product BRCA1 and mitotic regulators such as Aurora A, Nek2 and the Polo-like kinases Plk1 and Plk3. However, many missing links and discrepancies between different model systems remain.
authors.affiliation: Clinical Cooperation Unit for Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Löffler
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
mesh_terms: D000818:Animals; D018385:Centrosome / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D043171:Chromosomal Instability; D004249:DNA Damage; D016678:Genome; D006801:Humans; D008938:Mitosis; D008957:Models, Genetic; D011494:Protein Kinases / Q000502:physiology
chemical_list: D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1