The polymorphic fungus Candida albicans switches from yeast to filamentous growth in response to a range of genotoxic insults, including inhibition of DNA synthesis by hydroxyurea (HU) or aphidicolin (AC), depletion of the ribonucleotidereductase subunit Rnr2p, and DNA damage induced by methylmethane sulfonate (MMS) or UV light (UV). Deleting RAD53, which encodes a downstream effector kinase for both the DNA-replication and DNA-damage checkpoint pathways, completely abolished the filamentous growth caused by all the genotoxins tested. Deleting RAD9, which encodes a signal transducer of the DNA-damage checkpoint, specifically blocked the filamentous growth induced by MMS or UV but not that induced by HU or AC. Deleting MRC1, the counterpart of RAD9 in the DNA-replication checkpoint, impaired DNA synthesis and caused cell elongation even in the absence of external genotoxic insults. Together, the results indicate that the DNA-replication/damage checkpoints are critically required for the induction of filamentous growth by genotoxic stress. In addition, either of two mutations in the FHA1 domain of Rad53p, G65A, and N104A, nearly completely blocked the filamentous-growth response but had no significant deleterious effect on cell-cycle arrest. These results suggest that the FHA domain, known for its ability to bind phosphopeptides, has an important role in mediating genotoxic-stress-induced filamentous growth and that such growth is a specific, Rad53p-regulated cellular response in C. albicans. INTRODUCTIONThe polymorphic fungus Candida albicans has proven to be a very useful model for the study of cell morphogenesis (Odds, 1994;Sudbery et al., 2004;Wightman et al., 2004;Zheng et al., 2004). This organism can switch between several morphological forms including yeast, pseudohyphae, and hyphae (Berman and Sudbery, 2002;Sudbery et al., 2004). The yeast-hypha transition has attracted much attention because of its established importance for infection and virulence (Csank et al., 1997;Lo et al., 1997;Gale et al., 1998;Gow et al., 2002;Zheng et al., 2004). Several signal-transduction pathways are known to play roles in growth-form selection (Liu, 2001;Berman and Sudbery, 2002). The cAMPprotein kinase A (PKA) pathway has a key role, because blocking it abolishes true hyphal growth under most experimental conditions (Lo et al., 1997;Stoldt et al., 1997;Rocha et al., 2001). Another important pathway contains a MAPkinase cascade that seems to have a more important role in regulating pseudohyphal than true hyphal growth (Liu et al., 1994). The two pathways control the transcription factors Efg1p and Cph1p, respectively, which activate the expression of hypha-specific genes for a suite of infection-related functions (Lane et al., 2001).A diverse range of environmental stimuli can induce C. albicans hyphal or pseudohyphal growth, such as serum, neutral pH, appropriate temperature, certain amino acids and sugars, and some synthetic growth media (Ernst, 2000;Sudbery et al., 2004). These conditions more-or-less mimic certain host c...