Overview
Research in the Andreassen Laboratory at Cincinnati Children’s Hospital Medical Center focuses on the relationship of DNA repair and cell cycle checkpoints to the genetic instability that underlies the development of cancer. In particular, we are studying basic cellular mechanisms that respond to DNA damage, including breast cancer susceptibility (BRCA) and Fanconi anemia (FA) genes and proteins. Each of these genes prevents chromosome instability and promotes resistance to DNA interstrand crosslinking agents, such as mitomycin C (MMC).
FA is associated with aplastic anemia, congenital anomalies, and a predisposition to leukemia and other cancers. At present, thirteen FA genes have been identified. Eight of the FA genes form a nuclear core complex that is required for the monoubiquitination of FANCD2 and FANCI, which is a key step in the FA-BRCA pathway.
Some of the BRCA genes, including FANCJ/BRIP1, FANCN/PALB2, and FANCD1/BRCA2, are also FA genes but are not required for FANCD2 monoubiquitination. Their functional relationship to other FA proteins is not well understood. BRIP1 is a helicase first identified by its association with another breast cancer susceptibility protein, BRCA1. PALB2 regulates the recruitment of BRCA2 to sites of DNA damage and both have a critical role in regulating DNA repair by homologous recombination. Our goal is to understand the function of FA/BRCA proteins in DNA damage responses and to apply this knowledge to improving approaches to cancer therapy.
Areas of Research
- Regulation of FANCD2 monoubiquitination by the ATR checkpoint kinase and determination of FANCD2’s function in chromatin.
Regulation by ATR suggests a possible function of FA proteins at the replication fork.Also, to better understand the function of FANCD2 and the FA pathway,we are investigating the function of FANCD2 DNA damage foci that assemble in chromatin.
- Interactions of BRCA proteins and FANCN/PALB2 as a linker of BRCA1 and BRCA2. We are interested in understanding the regulation of the BRCA1-PALB2-BRCA2-RAD51 pathway of homologous recombination and believe that these studies should be applicable to personalized cancer therapy. Along with others, we have identified PALB2 as a physical and functional linker of BRCA1 and BRCA2.
- Relationship of FANCJ/BRIP1 to other FA proteins.
These studies should be important in elucidating the collective function of FA proteins to cellular responses to DNA damage and should better define the functional relationship between FA and BRCA proteins.
- Role of FA-BRCA proteins in alternative lengthening of telomeres (ALT) in the absence of telomerase.
We have recently demonstrated that FANCD2 monoubiquitination regulates the association of FANCD2 with ALT telomeres and is required for telomere maintenance at this site by homologous recombination. Thus, ALT cells may be useful for dissecting the function of FA/BRCA proteins in homologous recombination.
Publications
Andreassen, P.R., D'Andrea, A.D., and Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004 18 :1958-63.
Wang, X.Z., Andreassen, P.R., and D'Andrea, A.D. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol. 2004 24 :5850-62.
Zhang F, Fan Q, Ren K and Andreassen PR. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res. 2009 7:1110-18.
Cantor SB, Andreassen PR. Assessing the link between BACH1 and BRCA1 in the FA pathway. Cell Cycle. 2006 5:164-167.
Fan, Q.,Zhang,F., Barrett,B., Ren,K., and Andreassen,P.R. A role for monoubiquitinated FANCD2 at telomeres in ALT cells.
Nucl Acids Res. 2009 37:1740-54.
Andreassen PR and Ren K. Fanconi anemia proteins, DNA interstrand crosslink repair pathways, and cancer therapy. Curr Cancer Drug Targets. 2009 9:101-17.
