The Department of Biochemistry and Biophysics and the Wilmot Cancer Center at the University of Rochester Medical Center invite applications for a tenure track position in eukaryotic DNA repair and genome stability at the Assistant Professor level or higher. Applicants employing genetic methods in mammalian systems are preferred, but those in areas complementing existing strengths in cell signaling, cancer cell biology and biochemistry of DNA repair and chromatin are also invited. Submit a CV, statement of research accomplishments and plans and letters of recommendation to:

Robert Bambara
Repair Search
Dept. of Biochemistry and Biophysics
University of Rochester Medical Center
601 Elmwood Ave., Box 712
Rochester, NY 14642

Receipt of all applications will be acknowledged promptly. The University of Rochester is an equal opportunity/affirmative action educator and employer.

• Mechanism and Regulation of DNA Replication and Repair

• Nonsense-mediated mRNA Decay in Mammals: Dependence on Nuclear & Cytoplasmic RNA Processes ; Staufen1-mediated mRNA decay: A New mRNA Decay Pathway Used by Cells to Down-regulate Gene Expression  

Postdoctoral Position with Dr. Bambara

Regulation of DNA Replication and Repair. An important area of nvestigation relating to both aging and cancer is the study of mechansims by which mammalian cells coordinate DNA replication and repair, so that damage is repaired before it is passed on to progeny. We are reconstituting the reactions of mammalian Okazaki fragment processing and base excision repair. We recently found that replication protein A greatly stimulates base excision repair and hypothesize that it serves a factor that coordinates the actions of the proteins involved. We are trying to determine the complex function of this protein. The Dna2 protein is both a helicase and nuclease. It is essential for DNA replication but what it does is still unknown. Its biochemical properties are similar to those of FEN1, yet FEN1 cannot be its substitute. We are trying to understand the nature of its essential contribution. The signaling protein p21cip1 is thought to mediate a shift from DNA replication to repair during chromosomal damage. It might do so by binding PCNA. Yet PCNA is involved in both processes. We are trying to determine the mechanism of regulation by p21cip1. The project involves training in protein expression, reconstitution of replication and repair pathways, structural analysis and mutagenesis of proteins, cell culture, and mechanisms of catalysis, regulation and signaling.
     Recombination in HIV. The two chromosomes in HIV frequently recombine during replication, a process that evolves viral fitness in a highly undesirable manner. We found that recombination is so efficient because the two chromosomes bind to each other. This binding is most favorable at hairpins, and is stabilized by a process called kissing. The geometry of the loops on some hairpins particularly favor the kissing interaction. The interaction has the ability to propagate along the genome stabilizing many binding sites. The DNA strand being copied from one genome transfers to the other at these sites. We are using genetic modification of the sequence and structure of the RNA to probe the recombination mechanism both in vitro and in vivo. Results will give us a lot of information about RNA-RNA interaction, the mechanism of recombination and the unique evolution of HIV. The project involves reconstitution of recombination in vitro, measurement of RNA-RNA folding and interaction, studies of reverse transcriptase reaction mechanisms and cell culture.
     Call: (585) 275-2764, University of Rochester Medical Center, Department of Biochemistry & Biophysics, 601 Elmwood Ave., Box 712, Rochester, NY 14642. Applicants should send three letters of recommendation and be prepared to speak on their thesis work. 

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Postdoctoral Positions with Dr. Maquat 

A post-doctoral position is available to study the mechanism by which termination (nonsense) codons elicit nonsense-mediated mRNA decay (NMD) in mammalian cells. Nonsense codons, caused by either frameshift or nonsense mutations, are responsible for an estimated one-third of inherited genetic diseases. We are particularly interested in understanding the changes in mRNP structure that occur during the pioneer round of translation and how the pioneer initiation complex is remodeled to the steady-state initiation complex.

NMD is a splicing-dependent and translation-dependent pathway that targets not only disease-associated but also naturally occurring transcripts (for recent review, see Isken and Maquat, 2007, Genes & Dev. 21:1833-3856), many of which are mistakes made during alternative splicing (Pan et al., 2006, Genes & Dev . 20:153-8). Currently, we are interested in further characterizing the pioneer round of translation, during which nonsense codon recognition leads to NMD (Ishigaki et al., 2001 Cell 106:607-617; Lejeune et al., 2002, EMBO J. 21:3536-3545). We have made important progress in identifying components of the pioneer translation initiation complex, which consists of CBP80/20 at the mRNA cap, PABP2 and PABP1 at the mRNA poly(A) tail, and the exon junction complex of proteins that includes the NMD factors Upf3 or Upf3X, Upf2, and, finally, Upf1 (Chiu et al., 2004, Genes & Dev. 18:645-754; Lejeune et al., 2004, Nat. Struct. Mol. Biol. 11:992-1000; Hosoda et al., 2006, Mol. Cell. Biol. 26:3085-3097). We have found that CBP80 promotes NMD by promoting the interaction between Upf1 and Upf2 (Hosoda et al., 2005, Nat. Struct. Mol. Biol. 12:893-901). We are also interested in understanding the mechanistic difference between nucleus-associated and cytoplasmic NMD, the degradative enzymology of NMD (Lejeune et al., 2003, Mol. Cell 12:675-687), and factor function in NMD (Chiu et al., 2003, RNA 9:77-87; Brumbaugh et al., 2004, Mol. Cell 14:585-598; Matsuda et al., 2007, Nat. Struct. Mol. Biol. 14:974-979).

Opportunities are also available to study a related mRNA decay pathway that we recently uncovered (Kim et al., 2005, Cell 120:195-208; Kim et al., 2007, EMBO J. 26:2670-2681). This pathway, which we call Staufen1-mediated mRNA decay (SMD) , has opened up a whole new field of research for us. We have found that Staufen1, which is a double-stranded RNA binding protein, recruits the NMD factor Upf1 to certain mRNA 3’ untranslated regions so as to elicit SMD in a translation-dependent fashion. Using microarray analyses, we have identified a number of mRNAs that are naturally down-regulated by SMD. Future studies aim to elucidate how mammalian cells utilize SMD to regulate gene expression. Included in these studies is identifying mRNA sequences that bind Staufen1, defining the Staufen1-containing mRNA binding complex, and characterizing the physiological significance of SMD. Unlike NMD, SMD targets not only CBP80/20-bound mRNA but also its rearranged product, eIF4E-bound mRNA. This makes sense for a conditionally regulated pathway.

Successful candidates will join a well-equipped group of interactive lab members with diverse backgrounds and broad expertise in newly remodeled labs. The University of Rochester is unique for its sizeable community of RNA researchers.

Interested individuals should send a C.V., including a description of past and on-going research, and the names and contact information of three references to: