Since cdc48 mutants were isolated by the first genetic screens for cell division cycle (cdc) mutants in yeast, the requirement of the chaperone-like ATPase Cdc48/p97 during cell division has remained unclear. Here, we discover an unanticipated function for Caenorhabditis elegans CDC-48 in DNA replication linked to cell cycle control. Our analysis of the CDC-48 UFD؊1/NPL؊4 complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms. These developmental defects result from activation of the DNA replication checkpoint caused by replication stress. Similar to loss of replication licensing factors, DNA content is strongly reduced in worms depleted for CDC-48, UFD-1, and NPL-4. In addition, these worms show decreased DNA synthesis and hypersensitivity toward replication blocking agents. Our findings identified a role for CDC-48 UFD؊1/NPL؊4 in DNA replication, which is important for cell cycle progression and genome stability.ATL-1/ATR ͉ C. elegans ͉ CDC-48/p97 ͉ genome stability M any biological processes including development and cell division are tightly controlled by ubiquitin-mediated protein degradation. A central factor for mobilizing and targeting ubiquitylated substrates to the 26S proteasome is Cdc48/p97 (Cdc48 in yeast, CDC-48 in C. elegans, p97 in mammals), a chaperone-like AAA ATPase (1). Its activity is modulated by alternative adaptor proteins, which determine recruitment and processing of specific substrates. Cdc48/p97 forms a complex with the cofactors Ufd1 and Npl4 that is involved in endoplasmic reticulum (ER)-associated protein degradation (ERAD) (2), membrane fusion and cell cycle progression (3, 4). Temperature sensitive cdc48 mutants have already been isolated by early cdc-screens (5) in Saccharomyces cerevisiae. However, the essential role of Cdc48 during cell cycle progression remained elusive.Meanwhile, different activities of Cdc48/p97 in mitosis have been addressed by several studies. Early observations in yeast and recent findings using Xenopus egg extracts suggested that Cdc48/p97 regulates spindle disassembly during exit from mitosis (6, 7). For example, spindle regulators such as the Polo-like kinase Plx remain attached and probably stabilize the spindle in the absence of p97 Ufd1/Npl4 . However, contradictory evidence exists concerning a specific role of the p97 Ufd1/Npl4 complex in spindle dynamics (8,9). Beside spindle function, p97 together with its Ufd1-Npl4 cofactor is important for nuclear envelope assembly (10). Interestingly, it has been shown that p97 stimulates nucleus reformation after mitosis by extracting and thereby inactivating the mitotic progression kinase Aurora B from chromatin (11). Together, these diverse processes involving Cdc48/p97 suggest the existence of multiple substrates that need to be regulated during mitosis.Recently, we found that the C. elegans Cdc48/p97 homologues CDC-48.1 and CDC-48.2 form an evolutionarily conserved complex with UFD-1 and NPL-4 important for t...
SummaryPHD1 belongs to the family of prolyl-4-hydroxylases (PHDs) that is responsible for posttranslational modification of prolines on specific target proteins. Because PHD activity is sensitive to oxygen levels and certain byproducts of the tricarboxylic acid cycle, PHDs act as sensors of the cell’s metabolic state. Here, we identify PHD1 as a critical molecular link between oxygen sensing and cell-cycle control. We show that PHD1 function is required for centrosome duplication and maturation through modification of the critical centrosome component Cep192. Importantly, PHD1 is also required for primary cilia formation. Cep192 is hydroxylated by PHD1 on proline residue 1717. This hydroxylation is required for binding of the E3 ubiquitin ligase SCFSkp2, which ubiquitinates Cep192, targeting it for proteasomal degradation. By modulating Cep192 levels, PHD1 thereby affects the processes of centriole duplication and centrosome maturation and contributes to the regulation of cell-cycle progression.
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