Inherited or acquired deficiencies in genome stability pathways are known to cause a variety of human pathological conditions, including early onset cancer. The familial genome instability or cancer susceptibility syndrome, Fanconi Anemia (FA), is caused by mutations in 1 of at least 13 FA genes. Biallelic mutations in some of these genes also occur in cancers of non-FA patients, implicating these genes in tumor suppression or genome maintenance among the general population. These genes act in a common molecular pathway that modulates DNA repair, especially the repair of DNA interstrand cross-links. Protein ubiquitination and deubiquitination are dynamic processes implicated in the regulation of numerous cellular pathways. Monoubiquitination of the FA protein FANCD2 appears to be critical in the repair of DNA damage because many of the proteins that are mutated in FA are required for FANCD2 ubiquitination. By screening a gene family RNAi library, we identified a deubiquitinating enzyme as a novel component of the FA pathway. Despite the number of recent studies that have helped identify key players for the activation of the FA pathway, it is still unclear how the regulation of the FA pathway is achieved. The research conducted in my laboratory is directed towards understanding the delicate balance between the positive and negative regulators of ubiquitination in the FA pathway. The proposed research concerns enzymes of the ubiquitin system controlling DNA repair and genome stability. Accumulating evidence indicates that defects in the DNA damage response can lead to cancer initiation. The results of our studies will help to define the molecular mechanisms of the Fanconi Anemia pathway and how dysregulation of this pathway can lead to oncogenesis.

Public Health Relevance

The familial genome instability or cancer susceptibility syndrome, Fanconi Anemia (FA), is caused by mutations in 1 of at least 13 FA genes. Biallelic mutations in some of these genes also occur in cancers of non-FA patients, implicating these genes in tumor suppression or genome maintenance among the general population. The results of our studies will help to define the molecular mechanisms of the Fanconi Anemia pathway and how dysregulation of this pathway can lead to oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084244-04
Application #
8205032
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Krasnewich, Donna M
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$340,561
Indirect Cost
$139,640
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Karttunen, Heidi; Savas, Jeffrey N; McKinney, Caleb et al. (2014) Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth. Mol Cell 55:111-22
Bekes, Miklos; Okamoto, Keiji; Crist, Sarah B et al. (2013) DUB-resistant ubiquitin to survey ubiquitination switches in mammalian cells. Cell Rep 5:826-38
Jones, Mathew Jk; Colnaghi, Luca; Huang, Tony T (2012) Dysregulation of DNA polymerase ? recruitment to replication forks results in genomic instability. EMBO J 31:908-18
Colnaghi, Luca; Jones, Mathew J K; Cotto-Rios, Xiomaris M et al. (2011) Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair. Blood 117:2247-56
Cotto-Rios, Xiomaris M; Jones, Mathew J K; Huang, Tony T (2011) Insights into phosphorylation-dependent mechanisms regulating USP1 protein stability during the cell cycle. Cell Cycle 10:4009-16
Cotto-Rios, Xiomaris M; Jones, Mathew J K; Busino, Luca et al. (2011) APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage. J Cell Biol 194:177-86