Mechanisms controlling the integrity of replicating chromosomes
Marco Foiani.
IFOM, Istituto FIRC di Oncologia Molecolare & University of Milan, Via Adamello 16, 20139 Milan, Italy.
In response to replication stress, the integrity of replication forks is preserved by the ATM and ATR-dependent checkpoint responses and by specialized SUMO and Ubiquitin pathways. Fork progression must be also controlled to maintain the integrity of the replisome–fork complexes at pausing sites, to coordinate replicon fusion at termination of DNA synthesis and to deal with the collision between transcription and replication.
DNA topoisomerases play crucial roles in facilitating fork progression during unperturbed DNA synthesis and in response to replication stress.
We used genomic approaches to identify chromosome replication-risk zones (CRZs) where replication forks pause, terminate or encounter transcription. We have analyzed the contribution of the replication checkpoint, of different DNA topoisomerases and HMG (High Mobility Group) proteins in preserving the integrity of CRZs during chromosome replication. We found that CRZs represent hot spots for aberrant chromosomal transitions and DNA breaks under pathological conditions. I will discuss how topological changes can assist the progression of replication forks.
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