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Helmholtz Munich | Stephan Hamperl

How origins of replication are organized by the cytoskeleton


Before a cell divides, the genomic content of a cell is duplicated during DNA replication. Each cell has many origins of replication (ORIs), but not all are active at the same time, and some fire earlier and some later. Combining their approach to isolate distinct replication origins from yeast chromosomes with a comprehensive proteomic analysis, researchers from the Institute for Epigenetics and Stem Cells could identify a novel factor that mechanistically connects replication timing and chromosomal organization with the microtubule cytoskeleton.

DNA replication is one of the most important and fundamental biological processes. Each time a cell divides, an exact copy of the genomic DNA has to be produced and inherited to the two daughter cells in order to give viable offsprings. Eukaryotic DNA replication starts at multiple sites throughout the genome named origins of replication. Interestingly, origins fire with highly variable efficiencies and timing during S-phase of the cell cycle, with some firing early-efficiently (EE) and others late-inefficiently (LI). The chromatin environment at origins of replication is thought to influence this behavior, but the molecular details of this regulation is unknown. 

In a recent study, a group of researchers led by Stephan Hamperl at Helmholtz Munich developed an efficient system to specifically excise and purify distinct replication origins from yeast chromosomes. The purity and yield of this single-locus chromatin purification approach allowed them to report a comprehensive proteomic analysis of selected EE and LI origins, revealing many known as well as novel origin-interacting chromatin factors. One of the unexpected interactors at origins was the Ask1 protein, a component of the so-called DASH complex that normally assembles into a microtubule-encircling ring and helps to attach microtubules to centromeric DNA. Most excitingly, the authors followed up on this factor and showed in functional experiments that Ask1/DASH is indeed regulating the replication timing of selected replication origins. "Thus, our unbiased proteomic approach revealed a novel factor that mechanistically connects replication timing and chromosomal organization with the microtubule cytoskeleton.", says Stephan, the corresponding author of the work.

This work builds upon the research of the Hamperl lab that aims to understand how DNA replication is regulated on our genome without interfering with other cellular processes such as transcription.  

Further information:

Weiβ et al. (2023). Single-copy locus proteomics of early- and late-firing DNA replication origins identifies a role of Ask1/DASH complex in replication timing control. Cell Reports