Deciphering the role of chromatin remodeling in DNA damage repair and carcinogenesis

Our cells are faced with more than 10.000 DNA lesions per day. Failure to repair such lesions can lead to genomic instability, cancer development or cell death. Efficient repair of DNA damage, however, is complicated by the fact that genomic DNA is packaged, through histone and non-histone proteins, into a condensed structure called chromatin. The DNA repair machinery has to circumvent this natural barrier to gain access to damaged DNA and repair DNA lesions. I found that the INO80 chromatin remodeling complex helps to overcome this barrier at sites of DNA damage. INO80 is recruited to chromosomal DNA double-strand breaks to alter chromatin structure and facilitate access to the damaged DNA. However, along with INO80 more than 50 different proteins involved in diverse aspects of the cellular response to DNA damage are recruited to a chromosomal DNA double-strand break, yet the interplay between INO80 and any of these proteins is an enigma. Here, I propose biochemical and genetic approaches to identify and characterize the proteins that functionally interact with INO80 in order to decipher how chromatin remodeling complexes operate in the DNA damage response in both yeast and human cells. Moreover, a mouse model system will be used to study not only the physiological role of the INO80 enzyme, but also its effect on cancer development in response to DNA damage. These studies should gain insight into how chromatin remodeling complexes help cells to repair DNA damage in the context of chromatin and affect carcinogenesis.