October 2011

DNA replication, recombination and repair

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.



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