Doctor of Philosophy, Stanford University, BIO-PHD (2018)
Bachelor of Arts, Princeton University, Molecular Biology (2010)
Punctuated evolution and transitional hybrid network in an ancestral cell cycle of fungi
Although cell cycle control is an ancient, conserved, and essential process, some core animal and fungal cell cycle regulators share no more sequence identity than non-homologous proteins. Here, we show that evolution along the fungal lineage was punctuated by the early acquisition and entrainment of the SBF transcription factor through horizontal gene transfer. Cell cycle evolution in the fungal ancestor then proceeded through a hybrid network containing both SBF and its ancestral animal counterpart E2F, which is still maintained in many basal fungi. We hypothesize that a virally-derived SBF may have initially hijacked cell cycle control by activating transcription via the cis-regulatory elements targeted by the ancestral cell cycle regulator E2F, much like extant viral oncogenes. Consistent with this hypothesis, we show that SBF can regulate promoters with E2F binding sites in budding yeast.
View details for DOI 10.7554/eLife.09492
View details for Web of Science ID 000376602700001
View details for PubMedID 27162172
View details for PubMedCentralID PMC4862756
Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size.
2015; 526 (7572): 268-272
Cell size fundamentally affects all biosynthetic processes by determining the scale of organelles and influencing surface transport. Although extensive studies have identified many mutations affecting cell size, the molecular mechanisms underlying size control have remained elusive. In the budding yeast Saccharomyces cerevisiae, size control occurs in G1 phase before Start, the point of irreversible commitment to cell division. It was previously thought that activity of the G1 cyclin Cln3 increased with cell size to trigger Start by initiating the inhibition of the transcriptional inhibitor Whi5 (refs 6-8). Here we show that although Cln3 concentration does modulate the rate at which cells pass Start, its synthesis increases in proportion to cell size so that its total concentration is nearly constant during pre-Start G1. Rather than increasing Cln3 activity, we identify decreasing Whi5 activity--due to the dilution of Whi5 by cell growth--as a molecular mechanism through which cell size controls proliferation. Whi5 is synthesized in S/G2/M phases of the cell cycle in a largely size-independent manner. This results in smaller daughter cells being born with higher Whi5 concentrations that extend their pre-Start G1 phase. Thus, at its most fundamental level, size control in budding yeast results from the differential scaling of Cln3 and Whi5 synthesis rates with cell size. More generally, our work shows that differential size-dependency of protein synthesis can provide an elegant mechanism to coordinate cellular functions with growth.
View details for DOI 10.1038/nature14908
View details for PubMedID 26390151
View details for PubMedCentralID PMC4600446
The putative Poc complex controls two distinct Pseudomonas aeruginosa polar motility mechanisms
2013; 90 (5): 923-938
Each Pseudomonas aeruginosa cell localizes two types of motility structures, a single flagellum and one or two clusters of type IV pili, to the cell poles. Previous studies suggested that these motility structures arrive at the pole through distinct mechanisms. Here we performed a swimming motility screen to identify polar flagellum localization factors and discovered three genes homologous to the TonB/ExbB/ExbD complex that have defects in both flagella-mediated swimming and pilus-mediated twitching motility. We found that deletion of tonB3, PA2983 or PA2982 led to non-polar localization of the flagellum and FlhF, which was thought to sit at the top of the flagellar localization hierarchy. Surprisingly, these mutants also exhibited pronounced changes in pilus formation or localization, indicating that these proteins may co-ordinate both the pilus and flagellum motility systems. Thus, we have renamed PA2983 and PA2982, pocA and pocB, respectively, for polar organelle co-ordinator to reflect this function. Our results suggest that TonB3, PocA and PocB may form a membrane-associated complex, which we term the Poc complex. These proteins do not exhibit polar localization themselves, but are required for increased expression of pilus genes upon surface association, indicating that they regulate motility structures through either localization or transcriptional mechanisms.
View details for DOI 10.1111/mmi.12403
View details for Web of Science ID 000327374300002
View details for PubMedID 24102920
View details for PubMedCentralID PMC4666538
Cell Size Control in Yeast
2012; 22 (9): R350-R359
Cell size is an important adaptive trait that influences nearly all aspects of cellular physiology. Despite extensive characterization of the cell-cycle regulatory network, the molecular mechanisms coupling cell growth to division, and thereby controlling cell size, have remained elusive. Recent work in yeast has reinvigorated the size control field and suggested provocative mechanisms for the distinct functions of setting and sensing cell size. Further examination of size-sensing models based on spatial gradients and molecular titration, coupled with elucidation of the pathways responsible for nutrient-modulated target size, may reveal the fundamental principles of eukaryotic cell size control.
View details for DOI 10.1016/j.cub.2012.02.041
View details for Web of Science ID 000303967600019
View details for PubMedID 22575477
View details for PubMedCentralID PMC3350643