DNA and damage control: A complex web of players

2012

Challenge

Fanconi anemia (FA) is a genetic disease characterized by congenital defects, bone marrow failure, and cancer susceptibility. At least 15 genes are known to be involved in the disease Fanconi anemia, whose gene products normally constitute a DNA damage response network that is essential for repair of DNA strand damage. Understanding how FA proteins are recruited to the DNA damage sites could uncover new drug targets.

Advance

IRP investigators led by Zhijiang Yan, Ph.D., showed for the first time that the FA network is controlled by a novel ubiquitin signaling cascade initiated by the RNF8 ubiquitin ligase and its partner, UBC13, and mediated by FAAP20, a newly described component of the FA core complex.

Impact

Transmission of DNA damage signals is vital in setting the rate and extent of DNA repair during aging and the development of cancer. The newly discovered cascade is now a potential target for drug intervention: agonists that promote repair could aid in the function of aging cells, whereas antagonists that inhibit the cascade could disrupt DNA repair in cancer cells to make them more susceptible to chemotherapy.

Publications

Yan Z, Guo R, Paramasivam M, Shen W, Ling C, Fox D 3rd, Wang Y, Oostra AB, Kuehl J, Lee DY, Takata M, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Li L, Seidman MM, Wang W. (2012). A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network. Mol Cell. 47(1), 61-75.