Genomic stability is vital to sustain cell survival and to prevent errors in control of proliferation that often result in disease. To maintain genomic stability, highly conserved signaling pathways of DNA integrity checkpoints are required to ensure the activation of the pathways to delay cell cycle progression until DNA repair or replication is complete after genotoxic stress that leads to DNA damage or replication blocks.

Much of the work that has deciphered the DNA integrity checkpoints is from the study of the budding yeast Saccharomyces cerevisiae. At least two checkpoints are known to operate during S phase in budding yeast: a replication checkpoint, originally observed after a hydroxyurea (HU)-induced deoxynucleoside triphosphate depletion, which blocks the progression of S phase in the replicative forks from both early- and late-firing origins [1], and an intra-S phase checkpoint, which lowers the rate of DNA replication and slows cell cycle advance in response to DNA-damaging agents [2] [3]. Additionally, checkpoints that operate to censor the assembly of the mitotic spindle and to control progression through mitosis have been discovered [4].

Central to the DNA integrity checkpoints are the highly conserved S. cerevisiae PI3K -related protein kinases Tel1 and Mec1 (Figure 1), the mammalian homologs of ATM and ATR [5] [6]. When DNA damage is detected by sensor proteins Mec1 and Tel1, which signal through mediator Rad9 to downstream effectors Rad53 and Chk1 [7] to cause mitotic arrest in the G1 and G2 phases [8] [9][10], three components of the DNA replication machinery-Mrc1, Tof1, and Csm3-operate as the replication checkpoint mediators as opposed to Rad9 [8] [11][12] (Figure 1). Thus, during normal DNA replication, these mediators function differently from when they are activated as part of a checkpoint [11] [12][13][14][15][16][17]. Most recently, Ndd1, a new component whose activity is controlled by genotoxic stress, has been identified [18] [19][20]. During methyl methane sulfonate (MMS)-induced G2/M arrest, Ndd1 activity is blocked exclusively in a Mec1-Rad53-dependent manner. HU induces a cell cycle arrest that prevents cell cycle progression into S phase and inhibits Ndd1 activity by Mec1-Rad53 through unknown mechanisms (Figure 1).

Unlike the fission yeast Schizosaccharomyces pombe and higher eukaryotes whose cell cycle progression is paused in response to replication stress, principally by promoting inhibitory phosphorylation of the cyclin-dependent kinase (CDKs), S. cerevisiae blocks cell cycle progression by directly inhibiting origin firing and chromosome segregation [1] [21]

In S. cerevisiae, Cdc28, the mammalian equivalent of Cdk1, along with its associated cyclins (Clbs), appears to coordinate the cell cycle with bud morphogenesis [22][23] [24]. It seems reasonable that the checkpoints of morphogenesis and those of DNA integrity are interconnected to allow for the tight coordination of cell cycle advancement and morphogenesis because the presence of morphogenesis checkpoints permits the cell to monitor defects in bud morphology, bud formation, septin organization, cell size, and cell wall synthesis, as well as perturbations in the actin cytoskeleton [23] [25] [26][27][28].

Swe1, a S. cerevisiae homolog of mammalian and S. pombe Wee1, is central to the morphogenesis checkpoints [23]. In budding yeast, Swe1 phosphorylates and inhibits Clb-bound Cdc28 on the Tyr19 residue [29] (Figure 1), a modification that is abolished by Mih1, the mammalian and S. pombe Cdc25 homolog [30][31]. During a normal cell cycle, Swe1 accumulates in the S phase, becomes serially hyperphosphorylated [32][33], producing multiple isoforms, and undergoes ubiquitin-mediated degradation [31] [34][35][36]. Defects in septin filament assembly at the bud neck [32] [37][38][39][40], as well as perturbations in the cell size, bud formation, and the actin cytoskeleton [23] [25], cause hypophosphorylation and stabilization of Swe1 and, consequently, the Swe1-dependent inhibition of Clb-Cdc28. This Swe1-imposed G2 delay leads to elongated cells, as Clb-Cdc28 cannot induce the switch from polarized to isotropic growth during budding [23] [41][42] (Figure 1).

Several other Swe1 regulators have also been shown to influence morphogenesis. Hsl1, the S. pombe Nim1/Cdr1, is a primary negative regulator of Swe1 and is required for efficient Swe1 localization at the bud neck [24][37][43]. UnlikeNim1/Cdr1, which is capable of phosphorylating Wee1, Hsl1 is unable to phosphorylate Swe1 [44]. Cla4/PAK and Cdc5/Polo, which are sequentially targeted to the neck of bud, appear to be responsible for the stepwise phosphorylation and down-regulation of Swe1 [45]. Additionally, Hsl1 appears to function in concert with Hsl7 [32] [46][47], as the absence of either Hsl1 or Hsl7 radically lowers Swe1 phosphorylation in vivo and results in cell elongation. However, the finding that the need for the Hsl1-Hsl7 interaction in Swe1 degradation can be bypassed by tethering Swe1 to the septins provides evidence that Hsl1-Hsl7 has a downstream role involving the presentation of Swe1 to other regulators for targeting to the degradation pathway [48]. Moreover, Swe1 degradation is regulated by its interaction with Clb2-Cdc28, Cdc5/Polo, and Hsl1. Swe1, synthesized during the S and G2 phases, binds to Clb2-Cdc28, where it is protected from Cdc5-specific phosphorylation. In late G2, when the levels of Hsl1 and Cdc5 rise, Hsl1 leads to the dissociation of Swe1 from Clb2-Cdc28, enabling Cdc5 to phosphorylate Swe1, which leads to its ubiquitin-mediated degradation [49] [50]. Recently, it has been found that feedback between Swe1 and Cdc28 controls the Swe1 abundance following stress. Swe1 inhibits Cdc28, which in turn antagonizes Swe1 by promoting its transcriptional repression and its degradation. In cells with mature septin rings, stresses due to osmotic shock or actin depolymerization promote the ability of Swe1 to inhibit Cdc28 but do not directly stabilize Swe1, resulting in subsequent stabilization and accumulation of Swe1 via feedback [38] (Figure 1). A positive feedback loop in which Swe1 activity inhibits the CDK, which then ceases to target Swe1for degradation, is of physiological importance.

In S. cerevisiae, various conditions that slow DNA synthesis are responsible for the induction of filamentous differentiation through Mec1-Rad53-Swe1-Cdc28-Clb2, as has been demonstrated earlier [51]. Under restrictive temperatures, DNA polymerase and DNA ligase temperature-sensitive mutants induce filamentous growth. In addition to HU, MSS, a DNA-alkylating agent that can slow DNA replication fork progression [52], and ara-CMP, a potent inhibitor of yeast DNA polymerases [53], induce filamentous growth. Since the MAPK and cAMP signaling pathways mediate nitrogen starvation-induced filamentous growth in S. cerevisiae, their possible involvement in genotoxic stress-induced filamentous growth has been investigated. As FLO8 encodes a DNA-binding transcriptional regulator that serves as the effector for the cAMP pathway and TEC1 encodes a DNA binding transcriptional regulator that serves as the effector for the MAPK pathway, tec1?flo8D mutant cells defective in both signaling pathways were created to examine their responses to genotoxic stress. Cells of the tec1?flo8D mutant respond to genotoxic stress with normal filamentous growth [51]. Additionally, HU-induced filamentous growth shows dependence on Swe1 that is essential for nitrogen starvation-induced filamentous growth [51]. Moreover, DNA-damaging agents such as bleomycin, etoposide, and H2O2 fail to induce filamentous growth despite the fact that the Mec1-Rad53 DNA integrity checkpoint proteins can also be activated by DNA damage via the Rad9-Chk1-dpendent DNA damage response checkpoint [51], demonstrating that the Rad9-Chk1-dependent DNA checkpoint pathway is not required for the Mec1-Rad53-mediated filamentous growth. Taken together, DNA replication stress-induced filamentous growth, mediated through Mec1-Rad53-Swe1-Cdc28-Clb2, and nitrogen starvation-induced filamentous growth, mediated by the MAPK and cAMP signaling pathways, converge at Swe1 (Figure 1).

It is of great interest to know if the genotoxic stress-induced filamentous growth is conserved in other fungi, particularly the important opportunistic human fungal pathogen Candida albicans [54] [55], whose ability to switch between the yeast and filamentous forms (pseudohyphae or hyphae) is critical to its virulence [56]. Upon response to environmental cues such as temperature, serum, and pH, C. albicans can change from a yeast (isotropic) form of growth to a filamentous (polarized) type growth. Under genotoxic stresses, such as HU and MMS, C. albicans can also be triggered to initiate polarized growth [57] [58], suggesting a conservation between C. albicans and the budding yeast in genotoxic stress-induced filamentous growth. Importantly, hydrogen peroxide activates hyphal development through Rad53 [59], whereas deleting RAD53 abolishes genotoxic stress-induced filamentous growth in C. albicans [60]. In contrast, inactivation of mitotic recombination proteins such as Rad50, Rad51, Rad52, and Mre11 or Cln3, Clb2, or Clb4 cyclins stimulates constitutive polarized growth in C. albicans [57] [60] [61][62][63][64]. This implies that the DNA integrity network and cell cycle proteins may represent new regulators of filamentous growth in C. albicans . Interestingly, through the site-directed mutagenesis of Rad53, it was found that the functions of Rad53 in DNA repair and replication arrest can be separated from its role in genotoxic stress-induced polarized growth in C. albicans [58] [60][65]

It has been known that the Hsl1-Swe1-Cdc28 pathway is important for cell elongation of both the yeast and hyphal forms and for virulence in C. albicans [66]. However, the phosphorylation state of Tyr19 on Cdc28 between yeast and hyphal cells does not appear to be different [67], indicating that Tyr19 phosphorylation on Cdc28 may not be important for polarized growth in C. albicans and that Swe1, which phosphorylates Tyr19 on Cdc28, is not required for hyphal growth. Essentially, even though yeast cells lacking SWE1 are slightly rounder in shape than wild type cells, they form normal pseudohyphae and hyphae [68]. Cell cycle delays in response to DNA damage leading to polarized growth are partially dependent upon Swe1 [61] . These results suggest that genotoxic stress-induced filamentous growth is not or is only partially mediated by Swe1, unlike the Rad53-Swe1-dependent process observed in S. cerevisiae. It will be interesting to see if cells lacking SWE1 abolish genotoxic stress-induced filamentous growth in C. albicans. Intriguingly, DNA damage-induced filamentous growth involves but does not require the expression of hyphal-specific genes or the Cph1 and Efg1 transcription factors, which are downstream targets of the MAPK and cAMP signaling pathways, respectively [61]. Additionally, cells lacking both CPH1 and EFG1 can be induced to filamentous growth in response to HU [69] . Particularly, filastatin, a small molecule, has been found to block hyphal growth induced by serum, Spider media, and GlcNac but not by the genotoxic agent HU [70]. Filastatin inhibits the transcriptional activation of HWP1 [70], which is an early and essential event in the process of hyphal development [71]. Taken together, there may be a pathway that is dependent on Rad53 but independent of Swe1 and the MAPK/cAMP signaling pathways for the induction of filamentous growth in C. albicans (Figure 2). The rewiring of the genotoxic stress-induced filamentous growth pathway may be associated with the interaction of C. albicans with its host. Determination of the differences between the S. cerevisiae and C. albicans on the control of genotoxic stress-induced filamentous growth is important and has a potential in therapeutics.

Keywords: Yeast, DNA integrity checkpoint, Genotoxic stress, DNA replication stress, Morphogenesis

This work was supported by the grants from the Ministry of Science and Technology of Taiwan, Republic of China (NSC 97-2320-B-040-014-MY3 and NSC 101-2629-B-040-001-MY3) and from the National Health Research Institutes of Taiwan, Republic of China (NHRI-EX99-9808SI & NHRI-EX100-9808SI)

1. Santocanale C, Diffley JF. A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 1998 Oct 8;395(6702):615–8.   [CrossRef]   [Pubmed]    
2. Paulovich AG, Margulies RU, Garvik BM, Hartwell LH. RAD9, RAD17, and RAD24 are required for S phase regulation in Saccharomyces cerevisiae in response to DNA damage. Genetics 1997 Jan;145(1):45–62.   [Pubmed]    
3. Paulovich AG, Toczyski DP, Hartwell LH. When checkpoints fail. Cell 1997 Feb 7;88(3):315–21.   [CrossRef]   [Pubmed]    
4. Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005 Oct;5(10):773–85.   [CrossRef]   [Pubmed]    
5. Paulovich AG, Hartwell LH. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 1995 Sep 8;82(5):841–7.   [CrossRef]   [Pubmed]    
6. Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature 2000 Nov 23;408(6811):433–9.   [CrossRef]   [Pubmed]    
7. Putnam CD, Jaehnig EJ, Kolodner RD. Perspectives on the DNA damage and replication checkpoint responses in Saccharomyces cerevisiae. DNA Repair (Amst) 2009 Sep 2;8(9):974–82.   [CrossRef]   [Pubmed]    
8. Alcasabas AA, Osborn AJ, Bachant J, et al. Mrc1 transduces signals of DNA replication stress to activate Rad53. Nat Cell Biol 2001 Nov;3(11):958–65.   [CrossRef]   [Pubmed]    
9. Frei C, Gasser SM. The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication checkpoint and colocalizes with Rad53p in S-phase-specific foci. Genes Dev 2000 Jan 1;14(1):81–96.   [CrossRef]   [Pubmed]    
10. Myung K, Datta A, Kolodner RD. Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae. Cell 2001 Feb 9;104(3):397–408.   [CrossRef]   [Pubmed]    
11. Bando M, Katou Y, Komata M, et al. Csm3, Tof1, and Mrc1 form a heterotrimeric mediator complex that associates with DNA replication forks. J Biol Chem 2009 Dec 4;284(49):34355–65.   [CrossRef]   [Pubmed]    
12. Katou Y, Kanoh Y, Bando M, et al. S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 2003 Aug 28;424(6952):1078–83.   [CrossRef]   [Pubmed]    
13. Calzada A, Hodgson B, Kanemaki M, Bueno A, Labib K. Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev 2005 Aug 15;19(16):1905–19.   [CrossRef]   [Pubmed]    
14. Mohanty BK, Bairwa NK, Bastia D. The Tof1p-Csm3p protein complex counteracts the Rrm3p helicase to control replication termination of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 2006 Jan 24;103(4):897–902.   [CrossRef]   [Pubmed]    
15. Szyjka SJ, Viggiani CJ, Aparicio OM. Mrc1 is required for normal progression of replication forks throughout chromatin in S. cerevisiae. Mol Cell 2005 Sep 2;19(5):691–7.   [CrossRef]   [Pubmed]    
16. Tourrière H, Versini G, Cordón-Preciado V, Alabert C, Pasero P. Mrc1 and Tof1 promote replication fork progression and recovery independently of Rad53. Mol Cell 2005 Sep 2;19(5):699–706.   [CrossRef]   [Pubmed]    
17. Tanaka H, Katou Y, Yagura M, et al. Ctf4 coordinates the progression of helicase and DNA polymerase alpha. Genes Cells 2009 Jul;14(7):807–20.   [CrossRef]   [Pubmed]    
18. Edenberg ER, Vashisht A, Benanti JA, Wohlschlegel J, Toczyski DP. Rad53 downregulates mitotic gene transcription by inhibiting the transcriptional activator Ndd1. Mol Cell Biol 2014 Feb;34(4):725–38.   [CrossRef]   [Pubmed]    
19. Tavanti A, Gow NA, Maiden MC, Odds FC, Shaw DJ. Genetic evidence for recombination in Candida albicans based on haplotype analysis. Fungal Genet Biol 2004 May;41(5):553–62.   [CrossRef]   [Pubmed]    
20. Yelamanchi SK, Veis J, Anrather D, Klug H, Ammerer G. Genotoxic stress prevents Ndd1-dependent transcriptional activation of G2/M-specific genes in Saccharomyces cerevisiae. Mol Cell Biol 2014 Feb;34(4):711–24.   [CrossRef]   [Pubmed]    
21. Sánchez M, Calzada A, Bueno A. Functionally homologous DNA replication genes in fission and budding yeast. J Cell Sci 1999 Jul;112 ( Pt 14):2381–90.   [Pubmed]    
22. Keaton MA, Lew DJ. Eavesdropping on the cytoskeleton: progress and controversy in the yeast morphogenesis checkpoint. Curr Opin Microbiol 2006 Dec;9(6):540–6.   [CrossRef]   [Pubmed]    
23. Lew DJ. The morphogenesis checkpoint: how yeast cells watch their figures. Curr Opin Cell Biol 2003 Dec;15(6):648–53.   [CrossRef]   [Pubmed]    
24. Theesfeld CL, Zyla TR, Bardes EG, Lew DJ. A monitor for bud emergence in the yeast morphogenesis checkpoint. Mol Biol Cell 2003 Aug;14(8):3280–91.   [CrossRef]   [Pubmed]    
25. Harvey SL, Kellogg DR. Conservation of mechanisms controlling entry into mitosis: budding yeast wee1 delays entry into mitosis and is required for cell size control. Curr Biol 2003 Feb 18;13(4):264–75.   [CrossRef]   [Pubmed]    
26. Lew DJ, Reed SI. A cell cycle checkpoint monitors cell morphogenesis in budding yeast. J Cell Biol 1995 May;129(3):739–49.   [CrossRef]   [Pubmed]    
27. Lew DJ, Reed SI. Cell cycle control of morphogenesis in budding yeast. Curr Opin Genet Dev 1995 Feb;5(1):17–23.   [CrossRef]   [Pubmed]    
28. Suzuki M, Asada Y, Watanabe D, Ohya Y. Cell shape and growth of budding yeast cells in restrictive microenvironments. Yeast 2004 Sep;21(12):983–9.   [CrossRef]   [Pubmed]    
29. Booher RN, Deshaies RJ, Kirschner MW. Properties of Saccharomyces cerevisiae wee1 and its differential regulation of p34CDC28 in response to G1 and G2 cyclins. EMBO J 1993 Sep;12(9):3417–26.   [Pubmed]    
30. Russell P, Moreno S, Reed SI. Conservation of mitotic controls in fission and budding yeasts. Cell 1989 Apr 21;57(2):295–303.   [CrossRef]   [Pubmed]    
31. Sia RA, Herald HA, Lew DJ. Cdc28 tyrosine phosphorylation and the morphogenesis checkpoint in budding yeast. Mol Biol Cell 1996 Nov;7(11):1657–66.   [CrossRef]   [Pubmed]    
32. Shulewitz MJ, Inouye CJ, Thorner J. Hsl7 localizes to a septin ring and serves as an adapter in a regulatory pathway that relieves tyrosine phosphorylation of Cdc28 protein kinase in Saccharomyces cerevisiae. Mol Cell Biol 1999 Oct;19(10):7123–37.   [CrossRef]   [Pubmed]    
33. Sreenivasan A, Kellogg D. The elm1 kinase functions in a mitotic signaling network in budding yeast. Mol Cell Biol 1999 Dec;19(12):7983–94.   [CrossRef]   [Pubmed]    
34. Kaiser P, Sia RA, Bardes EG, Lew DJ, Reed SI. Cdc34 and the F-box protein Met30 are required for degradation of the Cdk-inhibitory kinase Swe1. Genes Dev 1998 Aug 15;12(16):2587–97.   [CrossRef]   [Pubmed]    
35. McMillan JN, Theesfeld CL, Harrison JC, Bardes ES, Lew DJ. Determinants of Swe1p degradation in Saccharomyces cerevisiae. Mol Biol Cell 2002 Oct;13(10):3560–75.   [CrossRef]   [Pubmed]    
36. Thornton BR, Toczyski DP. Securin and B-cyclin/CDK are the only essential targets of the APC. Nat Cell Biol 2003 Dec;5(12):1090–4.   [CrossRef]   [Pubmed]    
37. Barral Y, Parra M, Bidlingmaier S, Snyder M. Nim1-related kinases coordinate cell cycle progression with the organization of the peripheral cytoskeleton in yeast. Genes Dev 1999 Jan 15;13(2):176–87.   [CrossRef]   [Pubmed]    
38. King K, Kang H, Jin M, Lew DJ. Feedback control of Swe1p degradation in the yeast morphogenesis checkpoint. Mol Biol Cell 2013 Apr;24(7):914–22.   [CrossRef]   [Pubmed]    
39. McMillan JN, Longtine MS, Sia RA, et al. The morphogenesis checkpoint in Saccharomyces cerevisiae: cell cycle control of Swe1p degradation by Hsl1p and Hsl7p. Mol Cell Biol 1999 Oct;19(10):6929–39.   [CrossRef]   [Pubmed]    
40. McMillan JN, Sia RA, Bardes ES, Lew DJ. Phosphorylation-independent inhibition of Cdc28p by the tyrosine kinase Swe1p in the morphogenesis checkpoint. Mol Cell Biol 1999 Sep;19(9):5981–90.   [CrossRef]   [Pubmed]    
41. Pruyne D, Bretscher A. Polarization of cell growth in yeast. J Cell Sci 2000 Feb;113 ( Pt 4):571–85.   [Pubmed]    
42. Pruyne D, Bretscher A. Polarization of cell growth in yeast. I. Establishment and maintenance of polarity states. J Cell Sci 2000 Feb;113 ( Pt 3):365–75.   [Pubmed]    
43. Ma XJ, Lu Q, Grunstein M. A search for proteins that interact genetically with histone H3 and H4 amino termini uncovers novel regulators of the Swe1 kinase in Saccharomyces cerevisiae. Genes Dev 1996 Jun 1;10(11):1327–40.   [CrossRef]   [Pubmed]    
44. Cid VJ, Shulewitz MJ, McDonald KL, Thorner J. Dynamic localization of the Swe1 regulator Hsl7 during the Saccharomyces cerevisiae cell cycle. Mol Biol Cell 2001 Jun;12(6):1645–69.   [CrossRef]   [Pubmed]   
45. Sakchaisri K, Asano S, Yu LR, et al. Coupling morphogenesis to mitotic entry. Proc Natl Acad Sci U S A 2004 Mar 23;101(12):4124–9.   [CrossRef]   [Pubmed]    
46. Asano S, Park JE, Sakchaisri K, et al. Concerted mechanism of Swe1/Wee1 regulation by multiple kinases in budding yeast. EMBO J 2005 Jun 15;24(12):2194–204.   [CrossRef]   [Pubmed]    
47. Longtine MS, Theesfeld CL, McMillan JN, Weaver E, Pringle JR, Lew DJ. Septin-dependent assembly of a cell cycle-regulatory module in Saccharomyces cerevisiae. Mol Cell Biol 2000 Jun;20(11):4049–61.   [CrossRef]   [Pubmed]    
48. King K, Jin M, Lew D. Roles of Hsl1p and Hsl7p in Swe1p degradation: beyond septin tethering. Eukaryot Cell 2012 Dec;11(12):1496–502.   [CrossRef]   [Pubmed]    
49. Simpson-Lavy KJ, Brandeis M. Cdk1 and SUMO regulate Swe1 stability. PLoS One 2010 Dec 6;5(12):e15089.   [CrossRef]   [Pubmed]    
50. Simpson-Lavy KJ, Brandeis M. Clb2 and the APC/C(Cdh1) regulate Swe1 stability. Cell Cycle 2010 Aug 1;9(15):3046–53.   [CrossRef]   [Pubmed]    
51. Jiang YW, Kang CM. Induction of S. Induction of S. cerevisiae filamentous differentiation by slowed DNA synthesis involves Mec1, Rad53 and Swe1 checkpoint proteins. Mol Biol Cell 2003 Dec;14(12):5116–24.   [CrossRef]   [Pubmed]    
52. Tercero JA, Diffley JF. Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 2001 Aug 2;412(6846):553–7.   [CrossRef]   [Pubmed]    
53. McIntosh EM, Kunz BA, Haynes RH. Inhibition of DNA replication in Saccharomyces cerevisiae by araCMP. Curr Genet 1986;10(8):579–85.   [CrossRef]   [Pubmed]    
54. Fidel PL Jr. History and update on host defense against vaginal candidiasis. Am J Reprod Immunol 2007 Jan;57(1):2–12.   [CrossRef]   [Pubmed]    
55. Pappas PG, Kauffman CA, Andes D, et al. Clnical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009 Mar 1;48(5):503–35.   [CrossRef]   [Pubmed]    
56. Noble SM, French S, Kohn LA, Chen V, Johnson AD. Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nat Genet 2010 Jul;42(7):590–8.   [CrossRef]   [Pubmed]    
57. Bachewich C, Whiteway M. Cyclin Cln3p links G1 progression to hyphal and pseudohyphal development in Candida albicans. Eukaryot Cell 2005 Jan;4(1):95–102.   [CrossRef]   [Pubmed]    
58. Loll-Krippleber R, d'Enfert C, Feri A, et al. A study of the DNA damage checkpoint in Candida albicans: uncoupling of the functions of Rad53 in DNA repair, cell cycle regulation and genotoxic stress-induced polarized growth. Mol Microbiol 2014 Feb;91(3):452–71.   [CrossRef]   [Pubmed]    
59. da Silva Dantas A, Patterson MJ, Smith DA, et al. Thioredoxin regulates multiple hydrogen peroxide-induced signaling pathways in Candida albicans. Mol Cell Biol 2010 Oct;30(19):4550–63.   [CrossRef]   [Pubmed]    
60. Shi QM, Wang YM, Zheng XD, Lee RT, Wang Y. Critical role of DNA checkpoints in mediating genotoxic-stress-induced filamentous growth in Candida albicans. Mol Biol Cell 2007 Mar;18(3):815–26.   [CrossRef]   [Pubmed]    
61. Andaluz E, Ciudad T, Gómez-Raja J, Calderone R, Larriba G. Rad52 depletion in Candida albicans triggers both the DNA-damage checkpoint and filamentation accompanied by but independent of expression of hypha-specific genes. Mol Microbiol 2006 Mar;59(5):1452–72.   [CrossRef]   [Pubmed]    
62. Bensen ES, Clemente-Blanco A, Finley KR, Correa-Bordes J, Berman J. The mitotic cyclins Clb2p and Clb4p affect morphogenesis in Candida albicans. Mol Biol Cell 2005 Jul;16(7):3387–400.   [CrossRef]   [Pubmed]    
63. García-Prieto F, Gómez-Raja J, Andaluz E, Calderone R, Larriba G. Role of the homologous recombination genes RAD51 and RAD59 in the resistance of Candida albicans to UV light, radiomimetic and anti-tumor compounds and oxidizing agents. Fungal Genet Biol 2010 May;47(5):433–45.   [CrossRef]   [Pubmed]    
64. Legrand M, Chan CL, Jauert PA, Kirkpatrick DT. Role of DNA mismatch repair and double-strand break repair in genome stability and antifungal drug resistance in Candida albicans. Eukaryot Cell 2007 Dec;6(12):2194–205.   [CrossRef]   [Pubmed]    
65. Sun LL, Li WJ, Wang HT, et al. Protein phosphatase Pph3 and its regulatory subunit Psy2 regulate Rad53 dephosphorylation and cell morphogenesis during recovery from DNA damage in Candida albicans. Eukaryot Cell 2011 Nov;10(11):1565–73.   [CrossRef]   [Pubmed]    
66. Umeyama T, Kaneko A, Nagai Y, et al. Candida albicans protein kinase CaHsl1p regulates cell elongation and virulence. Mol Microbiol 2005 Jan;55(2):381–95.   [CrossRef]   [Pubmed]    
67. Hazan I, Sepulveda-Becerra M, Liu H. Hyphal elongation is regulated independently of cell cycle in Candida albicans. Mol Biol Cell 2002 Jan;13(1):134–45.   [CrossRef]   [Pubmed]    
68. Wightman R, Bates S, Amornrrattanapan P, Sudbery P. In Candida albicans, the Nim1 kinases Gin4 and Hsl1 negatively regulate pseudohypha formation and Gin4 also controls septin organization. J Cell Biol 2004 Feb 16;164(4):581–91.   [CrossRef]   [Pubmed]    
69. Bachewich C, Thomas DY, Whiteway M. Depletion of a polo-like kinase in Candida albicans activates cyclase-dependent hyphal-like growth. Mol Biol Cell 2003 May;14(5):2163–80.   [CrossRef]   [Pubmed]    
70. Fazly A, Jain C, Dehner AC, et al. Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis. Proc Natl Acad Sci U S A 2013 Aug 13;110(33):13594–9.   [CrossRef]   [Pubmed]    
71. Lu Y, Su C, Wang A, Liu H. Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance. PLoS Biol 2011 Jul;9(7):e1001105.   [CrossRef]   [Pubmed]