Implications of DNA Replication Fork Proteins for Cancer (2009 - Present)
Investigator:Karen Almeida, Rhode IslandCollege Mentor: Susan
Gerbi, Brown University
Abstract:A unifying feature of cancer cells is
an unstable genome. To achieve normal development, a cell must
accurately coordinate pathways affecting DNA replication, chromosome
segregation and DNA damage repair. Mishaps in any of these procedures
can lead to instability in the genome and ultimately to a higher
incidence of cancer development. Therefore, these mechanisms must be
highly orchestrated and rigorously regulated. Accumulating evidence
demonstrates that there are particular molecules that bridge these
pathways to insure coordinate regulation. Many of these molecules have
overlapping functions for DNA replication and repair and chromosome
segregation. This grant application focuses on members of the RecQ
helicase superfamily of proteins that function at replication forks and
have roles in DNA repair and chromosome segregation.
Defects or mutations
in many RecQ family member genes manifest in human disease states. Bloom
Syndrome is a recessive disorder resulting from mutation in the Bloom
syndrome gene (Blm) and characterized by increased genomic instability and
enhanced onset of a wide array of cancer types. Blm plays a role in the
stabilization of stalled replication forks, often due to persistent DNA
damage during S phase. The protein biochemical studies proposed herein
will identify and refine the sub-domains of Blm responsible for
partnerships with known DNA repair and replication proteins such as Fen1,
BRCA1 and Nbs1.
Chl1p is a newly
identified RecQ family member in Drosophila and is implicated in bridging
DNA replication and chromosomal cohesion. This proposal seeks to study the
function of Chl1p in Drosophila by genetic deletion of the entire ORF for
Chl1p. Partial deletions of Chl1p will also be generated based on
information garnered from interaction studies of its human ortholog Blm.
Experiments herein span the disciplines of biochemistry, molecular biology
and genetics to investigate the RecQ protein partnerships responsible for
the accurate progression through DNA replication, repair and chromosome
segregation.