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 #
5R01GM084244-03
Application #
8006429
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
2011-01-01
Budget End
2011-12-31
Support Year
3
Fiscal Year
2011
Total Cost
$340,561
Indirect Cost
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Békés, Miklós; van der Heden van Noort, Gerbrand J; Ekkebus, Reggy et al. (2016) Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease. Mol Cell 62:572-85
Kee, Younghoon; Huang, Tony T (2016) Role of Deubiquitinating Enzymes in DNA Repair. Mol Cell Biol 36:524-44
Békés, Miklós; Rut, Wioletta; Kasperkiewicz, Paulina et al. (2015) SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme. Biochem J 468:215-26
Chen, Yu-Hung; Jones, Mathew J K; Yin, Yandong et al. (2015) ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. Mol Cell 58:323-38
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
Békés, Miklós; Okamoto, Keiji; Crist, Sarah B et al. (2013) DUB-resistant ubiquitin to survey ubiquitination switches in mammalian cells. Cell Rep 5:826-38
Cotto-Rios, Xiomaris M; Békés, Miklós; Chapman, Jessica et al. (2012) Deubiquitinases as a signaling target of oxidative stress. Cell Rep 2:1475-84
Jones, Mathew J K; Huang, Tony T (2012) The Fanconi anemia pathway in replication stress and DNA crosslink repair. Cell Mol Life Sci 69:3963-74
Piatkov, Konstantin I; Colnaghi, Luca; Bekes, Miklos et al. (2012) The auto-generated fragment of the Usp1 deubiquitylase is a physiological substrate of the N-end rule pathway. Mol Cell 48:926-33
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

Showing the most recent 10 out of 13 publications