Chromatin re-organization in response to replication stress

Background and Unmet Need

The mammalian genome is a highly organized structure where distinct chromosomal domains occupy discrete territories and position in a non-random fashion. Genome organization also determines the proper functioning of various biological processes, including DNA replication.

Genome organization has been widely studied in the context of gene regulation, while recently the role of genome organization in mediating DNA damage repair at DSB sites has also come to light. However, there is scarce information on how newly replicating regions are organized in response to replication stress.

Hypothesis to be Tested

My hypothesis is that stalled replication forks, especially at the regions prone to acquire breaks, undergo compartmentalization/re-organization within the 3-D nuclear space in response to replication stress to allow efficient fork protection and fork restart ability.

Objectives

This unique multidisciplinary project will yield critical information to reveal hidden connections of chromatin organization, replication fork stability, and chemoresistance. With this ERC project, I will determine for the first time:

1. The mechanistic insights of chromatin organization changes mediated by chromatin remodeling activity in response to replication stress.
2. Identify novel chromatin mobilizers associated with replication forks.
3. Determine the significance of chromatin reorganization to cope with replication stress for establishing resistance towards chemotherapeutic drugs in cancer cells and patient samples.

Expected Outcomes

My project will not only advance our fundamental knowledge on spatial and temporal reorganization of chromatin architecture containing stressed replication forks, but it also has a high potential to contribute to identifying novel targets aimed at chromatin organizers that mediate resistance towards replication stress-inducing chemotherapeutics.