Biology

Dr. Devyani Haldar
The Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad

Abstract:

The replication machinery, or the replisome, encounter a variety of obstacles during the normal process of DNA replication including damaged template DNA and various chromosome regions considered to be difficult to replicate owing to the presence of DNA secondary structures and DNA-binding proteins. These conditions cause stalling of the replication fork, generating replication stress. Stalled forks are prone to collapse, which leads to genomic instability, a hallmark of cancer. Numerous studies have indicated that there are several mechanisms to detect, prevent and counter the deleterious effects of replication stress. It is generally thought that one of the important function of the replication checkpoint is to stabilize the replisome and replication fork structure upon replication stress. It is known that DNA replication and DNA damage checkpoints are activated on replication stress to slow or stall DNA replication and promote DNA repair. Recent studies have indicated that chromatin regulators may play active part in replication stress response. In fission yeast, Schizosaccharomyces pombe, a sirtuin family histone deacetylase (HDAC), Hst4, functions in the maintenance of genome stability by promoting cell survival during replicative stress. We have observed that Hst4 is downregulated during DNA damage stress. However, the mechanism and significance of this regulation is not known. The DNA damage response pathway consists of checkpoint sensors and effectors which senses the damage and signals for DNA repair and thus contributes to genomic integrity. We show that Hst4 is targeted for degradation by ATR/Rad3 checkpoint sensor kinase in response to replication stress. I will present data showing novel functional link between the checkpoint, sirtuin family HDAC and the replisome components showing crosstalk between chromatin regulator and the regulators replication stress response. The knowledge of such novel regulatory mechanism involving sirtuins during replication stress will be useful in designing therapeutics against diseases, such as cancer where sirtuins, checkpoint components and replisome components are deregulated.