Cancer cells are genetically unstable and often contain high levels of DNA damage due to replication stress. This difference with normal cells presents an opportunity for therapeutic intervention using synthetic lethal approaches targeting the DNA damage response (DDR) and other genome maintenance pathways. Identification of key DDR proteins, characterizing their function in genome maintenance pathways, and defining the context where they become essential for viability is critical. The proposed studies will examine the genome maintenance activities of SMARCAL1, a recently discovered DDR protein. SMARCAL1 is an SNF2 family of ATPases that is activated by binding to forked DNA structures. SMARCAL1 has an unusual annealing helicase activity and functions at stalled replication forks. Our preliminary data support the hypothesis that SMARCAL1 functions with other DDR proteins to maintain genome integrity during DNA replication stress and thereby prevent disease. We will test this hypothesis by completing three specific aims: (1) characterize the interactions of SMARCAL1 with specific DDR proteins and determine the function of these interactions;(2) evaluate the in vivo function of SMARCAL1 in the response to DNA replication stress and damage;and (3) characterize the role of SMARCAL1 in responding to oncogene-induced replication stress. Innovative biochemical and genetic approaches including a unique mouse model of SMARCAL1-loss of function are proposed. Completion of this project will define the functional consequences of SMARCAL1 interaction with DDR proteins, and the in vivo function of SMARCAL1 in responding to both drug and oncogene-induced replication stress. Importantly, the project combines the complementary expertise of two investigators, who by working together, will provide critical insight into replication stress and the DDR and will identify novel therapeutic avenues to exploit in the treatment of cancer.

Public Health Relevance

SMARCAL1 is a DNA damage response protein that acts to maintain genomic integrity during DNA replication. This research proposal uses both biochemical and genetic approaches to understand the mechanisms by which SMARCAL1 maintains genome integrity in response to both drugs and oncogenes that induce replication stress.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160432-02
Application #
8517046
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
2012-07-26
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$444,706
Indirect Cost
$159,470
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Carrillo, A M; Bouska, A; Arrate, M P et al. (2015) Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 34:846-56
Carroll, Clinton; Badu-Nkansah, Akosua; Hunley, Tracy et al. (2013) Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. Pediatr Blood Cancer 60:E88-90