Dr. Russell is a Vision Scientist in the Department of Surgical and Radiological Sciences at the University of California, Davis. His research interests include glaucoma, aqueous humor dynamics, cataract and the influence of biophysical cues on ocular cells. He has studied the trabecular meshwork extensively and has human meshwork cells to test experimental drugs in vitro.
Vision of a near future: Bridging the human health-environment divide. Toward an integrated strategy to understand mechanisms across species for chemical safety assessment.
Toxicol In Vitro. 2019 Oct 25;:104692
Authors: Rivetti C, Allen TEH, Brown JB, Butler E, Carmichael PL, Colbourne JK, Dent M, Falciani F, Gunnarsson L, Gutsell S, Harrill JA, Hodges G, Jennings P, Judson R, Kienzler A, Margiotta-Casaluci L, Muller I, Owen SF, Rendal C, Russell PJ, Scott S, Sewell F, Shah I, Sorrel I, Viant MR, Westmoreland C, White A, Campos B
There is a growing recognition that application of mechanistic approaches to understand cross-species shared molecular targets and pathway conservation in the context of hazard characterization, provide significant opportunities in risk assessment (RA) for both human health and environmental safety. Specifically, it has been recognized that a more comprehensive and reliable understanding of similarities and differences in biological pathways across a variety of species will better enable cross-species extrapolation of potential adverse toxicological effects. Ultimately, this would also advance the generation and use of mechanistic data for both human health and environmental RA. A workshop brought together representatives from industry, academia and government to discuss how to improve the use of existing data, and to generate new NAMs data to derive better mechanistic understanding between humans and environmentally-relevant species, ultimately resulting in holistic chemical safety decisions. Thanks to a thorough dialogue among all participants, key challenges, current gaps and research needs were identified, and potential solutions proposed. This discussion highlighted the common objective to progress toward more predictive, mechanistically based, data-driven and animal-free chemical safety assessments. Overall, the participants recognized that there is no single approach which would provide all the answers for bridging the gap between mechanism-based human health and environmental RA, but acknowledged we now have the incentive, tools and data availability to address this concept, maximizing the potential for improvements in both human health and environmental RA.
PMID: 31669395 [PubMed - as supplied by publisher]
Molecular basis of chromatin remodeling by Rhp26, a yeast CSB ortholog.
Proc Natl Acad Sci U S A. 2019 Mar 13;:
Authors: Wang W, Xu J, Limbo O, Fei J, Kassavetis GA, Chong J, Kadonaga JT, Russell P, Li B, Wang D
CSB/ERCC6 belongs to an orphan subfamily of SWI2/SNF2-related chromatin remodelers and plays crucial roles in gene expression, DNA damage repair, and the maintenance of genome integrity. The molecular basis of chromatin remodeling by Cockayne syndrome B protein (CSB) is not well understood. Here we investigate the molecular mechanism of chromatin remodeling by Rhp26, a Schizosaccharomyces pombe CSB ortholog. The molecular basis of chromatin remodeling and nucleosomal epitope recognition by Rhp26 is distinct from that of canonical chromatin remodelers, such as imitation switch protein (ISWI). We reveal that the remodeling activities are bidirectionally regulated by CSB-specific motifs: the N-terminal leucine-latch motif and the C-terminal coupling motif. Rhp26 remodeling activities depend mainly on H4 tails and to a lesser extent on H3 tails, but not on H2A and H2B tails. Rhp26 promotes the disruption of histone cores and the release of free DNA. Finally, we dissected the distinct contributions of two Rhp26 C-terminal regions to chromatin remodeling and DNA damage repair.
PMID: 30867290 [PubMed - as supplied by publisher]
Genetic Interaction Landscape Reveals Critical Requirements for Schizosaccharomyces pombe Brc1 in DNA Damage Response Mutants.
G3 (Bethesda). 2015;5(5):953-62
Authors: Sánchez A, Roguev A, Krogan NJ, Russell P
Brc1, which was first identified as a high-copy, allele-specific suppressor of a mutation impairing the Smc5-Smc6 holocomplex in Schizosaccharomyces pombe, protects genome integrity during normal DNA replication and when cells are exposed to toxic compounds that stall or collapse replication forks. The C-terminal tandem BRCT (BRCA1 C-terminus) domain of fission yeast Brc1 docks with phosphorylated histone H2A (γH2A)-marked chromatin formed by ATR/Rad3 checkpoint kinase at arrested and damaged replication forks; however, how Brc1 functions in relation to other genome protection modules remains unclear. Here, an epistatic mini-array profile reveals critical requirements for Brc1 in mutants that are defective in multiple DNA damage response pathways, including checkpoint signaling by Rad3-Rad26/ATR-ATRIP kinase, DNA repair by Smc5-Smc6 holocomplex, replication fork stabilization by Mrc1/claspin and Swi1-Swi3/Timeless-Tipin, and control of ubiquitin-regulated proteolysis by the COP9 signalosome (CSN). Exogenous genotoxins enhance these negative genetic interactions. Rad52 and RPA foci are increased in CSN-defective cells, and loss of γH2A increases genotoxin sensitivity, indicating a critical role for the γH2A-Brc1 module in stabilizing replication forks in CSN-defective cells. A negative genetic interaction with the Nse6 subunit of Smc5-Smc6 holocomplex indicates that the DNA repair functions of Brc1 and Smc5-Smc6 holocomplex are at least partially independent. Rtt107, the Brc1 homolog in Saccharomyces cerevisiae, has a very different pattern of genetic interactions, indicating evolutionary divergence of functions and DNA damage responses.
PMID: 25795664 [PubMed - in process]
Regulation of the Rhp26ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif.
Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18566-71
Authors: Wang L, Limbo O, Fei J, Chen L, Kim B, Luo J, Chong J, Conaway RC, Conaway JW, Ranish JA, Kadonaga JT, Russell P, Wang D
CSB/ERCC6 (Cockayne syndrome B protein/excision repair cross-complementation group 6), a member of a subfamily of SWI2/SNF2 (SWItch/sucrose nonfermentable)-related chromatin remodelers, plays crucial roles in gene expression and the maintenance of genome integrity. Here, we report the mechanism of the autoregulation of Rhp26, which is the homolog of CSB/ERCC6 in Schizosaccharomyces pombe. We identified a novel conserved protein motif, termed the "leucine latch," at the N terminus of Rhp26. The leucine latch motif mediates the autoinhibition of the ATPase and chromatin-remodeling activities of Rhp26 via its interaction with the core ATPase domain. Moreover, we found that the C terminus of the protein counteracts this autoinhibition and that both the N- and C-terminal regions of Rhp26 are needed for its proper function in DNA repair in vivo. The presence of the leucine latch motif in organisms ranging from yeast to humans suggests a conserved mechanism for the autoregulation of CSB/ERCC6 despite the otherwise highly divergent nature of the N- and C-terminal regions.
PMID: 25512493 [PubMed - indexed for MEDLINE]
Tonoplast-localized Abc2 transporter mediates phytochelatin accumulation in vacuoles and confers cadmium tolerance.
J Biol Chem. 2010 Dec 24;285(52):40416-26
Authors: Mendoza-Cózatl DG, Zhai Z, Jobe TO, Akmakjian GZ, Song WY, Limbo O, Russell MR, Kozlovskyy VI, Martinoia E, Vatamaniuk OK, Russell P, Schroeder JI
Phytochelatins mediate tolerance to heavy metals in plants and some fungi by sequestering phytochelatin-metal complexes into vacuoles. To date, only Schizosaccharomyces pombe Hmt1 has been described as a phytochelatin transporter and attempts to identify orthologous phytochelatin transporters in plants and other organisms have failed. Furthermore, recent data indicate that the hmt1 mutant accumulates significant phytochelatin levels in vacuoles, suggesting that unidentified phytochelatin transporters exist in fungi. Here, we show that deletion of all vacuolar ABC transporters abolishes phytochelatin accumulation in S. pombe vacuoles and abrogates (35)S-PC(2) uptake into S. pombe microsomal vesicles. Systematic analysis of the entire S. pombe ABC transporter family identified Abc2 as a full-size ABC transporter (ABCC-type) that mediates phytochelatin transport into vacuoles. The S. pombe abc1 abc2 abc3 abc4 hmt1 quintuple and abc2 hmt1 double mutant show no detectable phytochelatins in vacuoles. Abc2 expression restores phytochelatin accumulation into vacuoles and suppresses the cadmium sensitivity of the abc quintuple mutant. A novel, unexpected, function of Hmt1 in GS-conjugate transport is also shown. In contrast to Hmt1, Abc2 orthologs are widely distributed among kingdoms and are proposed as the long-sought vacuolar phytochelatin transporters in plants and other organisms.
PMID: 20937798 [PubMed - indexed for MEDLINE]