The Kerem lab focuses on two main research fields (For more information click on the links on the left):

 1. Genomic instability during early stages of cancer development 

Cancer development is a complex multi-step process, involving a wide network of cellular events. Genomic instability, a hallmark of most cancer cells, is a crucial mechanism which enables the acquirement of new characteristics required for tumorigenisity. During early stages of cancer development, genome instability is the result of global changes in the DNA replication program, transcription profiles and epigenetic marks, which all lead to perturbed DNA replication dynamics and DNA damage. We try to reveal the various factors that can affect DNA replication dynamics, driving replication stress conditions and chromosomal instability. Unfolding the molecular basis underling genome instability in cancer may open new potential prevention and therapeutic approaches

We also focus on specific human genomic loci defined as common fragile sites (CFSs), which are an intrinsic part of the normal human genome and are preferentially unstable under conditions of DNA replication stress. We study different aspects of the complex molecular basis underlying the instability at these sites by analyzing the replication dynamics and DNA damage along them.

2. Modifiers of the Cystic Fibrosis (CF) disease severity and response to treatments

CF is the most prevalent lethal genetic disease in Caucasians caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We are studying two molecular genetic mechanisms which act as modifiers on disease severity and response to therapy:

The splicing machinery - as a significant fraction of CF-causing mutations (10-15%) affects pre-mRNA splicing (class V mutations), leading to the generation of aberrantly spliced CFTR transcripts , we are now developing a targeted modulation approach aimed to correct the splicing pattern of CFTR transcripts, according to the specific mutation carried. This strategy will interfere with the aberrant CFTR splicing in patients carrying splicing variants/mutations leading to restoration of the CFTR function.

The homeostatic mechanisms nonsense mediated mRNA decay (NMD) pathway and the unfolded protein response (UPR) - 10-15% of CF-causing mutations are nonsense mutations which lead to premature termination codon (PTC) (class I mutations). Transcripts carrying PTCs are known to undergo degradation by the NMD pathway.  Various small molecules, which can read-through PTCs, permits translation of full-length proteins and can be used as a treatment for patients carrying this type of mutations. We have found a variable clinical response to read-through modulation in CF patients due to variable efficiencies of the NMD pathway.  We are currently investigating various regulatory networks involved in the NMD pathway, among them the UPR. We have found that different levels of UPR activation can affect NMD efficiencies and can influence the response of patients carrying PTCs to read-through modulation.