October 2011

DNA replication, recombination and repair

Meetings_DNAThe three Rs – DNA replication, recombination and repair – are at the heart of proliferation, evolution and maintenance of genomes. Impairment of these processes results in genome instability and mutations that lead to cancer and other diseases. The four stimulating sessions in this year’s theme will focus on homology-directed repair of DNA damage, the interplay between replication and other fundamental cellular processes, and the special challenges associated with the maintenance and protection of chromosome ends.

DNA repair 

The first session, “Mechanism and Regulation of DNA Repair,” focuses on various molecular aspects of the DNA homology-directed repair of damaged chromosomes.

Lorraine Symington (Columbia University) works with budding yeast to study the genetic mechanism of homologous recombination that is mediated by the RAD52 gene group and the involvement of recombination in DNA double-strand break repair, the maintenance of genetic stability and meiosis. She will discuss her recent work, which has shed light on the multifaceted role of several DNA helicases and nucleases in the early and late steps of the homologous recombination reaction.

Hiroshi Iwasaki (Tokyo Institute of Technology) will describe his biochemical reconstitution of homologous recombination reactions with recombinase proteins and their accessory factors from fission yeast. The detailed analyses of these reconstituted reactions have provided considerable insights into the mechanism and regulation of the early steps of homologous DNA repair and the resolution of DNA intermediates made by recombinase proteins.

Sua Myong (University of Illinois at Urbana-Champaign) has been at the forefront of applying single-molecule methodologies to examine the mechanism of action of DNA repair proteins and how the activities of DNA repair complexes are regulated. She will describe her recent work, which makes use of fluorescently labeled biomolecules and fluorescence cell imaging to define the mechanism of helicases and other enzymes involved in DNA repair and replication. 

DNA replication  

The second session, “DNA Replication Mechanism and Context,” highlights recent advances in our understanding of the assembly and regulation of replication complexes and explores the intricate interplay between replication and other nuclear processes.

John Diffley (Cancer Research UK) uses budding yeast and human cells to decipher the mechanism of DNA replication and its regulation at multiple levels.  Biochemical reconstitution of initiation complexes has advanced significantly our understanding of replication origin choice, licensing and replisome assembly. He will discuss recent findings from his lab, including molecular studies that elucidate how checkpoints regulate origin firing.

Mike O’Donnell (Rockefeller University) studies DNA replication and its coordination with other nuclear processes, such as transcription, recombination and repair in E. coli and human cells. Recent advances at his lab have shed light on how replication forks survive collisions with transcribing RNA polymerases and how the replication machinery directly participates in diverse repair events.

Prasad Jallepalli (Memorial Sloan-Kettering Cancer Center) is broadly interested in the mechanisms that control the fidelity of chromosome segregation. Orderly progression through mitosis requires intact sister chromatid cohesion, which is established during and influenced by DNA replication.  Single-molecule analysis has revealed that replication, in turn, is profoundly affected by cohesion, with defects in post-transcriptional modification of cohesin subunits compromising fork progression and leading to the accumulation of DNA damage.

Dependence of DNA replication on repair 

The third session, “Coupling of DNA Repair and Replication,” concerns the dependence of DNA replication on DNA repair and checkpoint pathways and how this functional linkage helps maintain genome stability.

Antony Carr (University of Sussex) uses fission yeast as a model to delineate the genetic mechanisms of DNA replication-restart and replication-fork repair pathways. His laboratory has developed a replication-fork arrest system that entails a replication termination sequence and an inducible protein factor that binds this sequence. He will discuss results showing a major involvement of homologous recombination in the restart of stalled DNA replication forks at the expense of frequent gross chromosomal rearrangements.

Fanconi anemia is a chromosomal instability syndrome that predisposes patients to cancer. The FA proteins function together to promote DNA damage tolerance and repair during S phase. Angelos Constantinou (French National Center for Scientific Research) will discuss his recent findings, which implicate the DNA translocase FANCM, mutated in FA patients of complementation group M, in the processing and remodeling of stalled DNA replication forks and in linking replication-fork restart and repair to checkpoint signaling.

Catherine Freudenreich (Tufts University) is interested in understanding the cellular mechanisms of triplet DNA repeat maintenance. The expansion of trinucleotide repeat sequences is the cause of a number of inherited diseases, including Huntington’s disease (a degenerative neurological disease), Fragile X syndrome (the most common inherited mental retardation) and myotonic dystrophy (a type of muscular dystrophy). She will discuss how her work in the budding yeast sheds light on the mechanisms that cooperate to maintain DNA repeat length.




Telomeres and telomerase 

The final session, “Telomeres and Telomerase,” will focus on the challenges associated with the maintenance and protection of the ends of linear chromosomes.

Julie Cooper (Cancer Research UK, London) uses fission yeast to decipher the roles of telomeres in maintaining genome integrity and in guiding chromosomes through meiosis. Her recent work has uncovered a novel mechanism of chromosome end capping in cells that lack functional telomerase.

Madalena Tarsounas (Cancer Research UK, Oxford) studies how proteins involved in homologous recombination contribute to telomere replication and the establishment of protective cap structures. She will discuss results that implicate the tumor suppressor BRCA2 and the Rad51 recombinase in the maintenance of telomere integrity.

Telomerase has long been viewed as an attractive target for anti-cancer drugs, yet we still know little about the regulation of this enzyme. Peter Baumann (Stowers Institute) is interested in how the activity of this ribonucleoprotein complex is controlled at multiple levels from transcriptional regulation and complex assembly to posttranscriptional modifications and recruitment.

Meetings_DNA_BaumannMeetings_DNA_SungPeter Baumann (peb@stowers.org) is an associate investigator at the Stowers Institute for Medical Research, and Patrick Sung (Patrick.Sung@yale.edu) is professor at Yale University School of Medicine.

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