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**2** 

Wei Du

*USA* 

**Inflammatory ROS in Fanconi Anemia** 

**Hematopoiesis and Leukemogenesis** 

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure (BMF), clonal proliferation of hematopoietic stem cells, and transformation to leukemia and other cancers (Ames *et al.,* 1995; Boglilo *et al.,* 2002; Cohen-Haguenauer *et al.,* 2006; Cumming *et al.,* 2001; Fagerlie *et al.,* 2001; Jonkers *et al.,* 2001; Suematsu *et al.,* 2003). Somatic cell fusion studies show FA is genetically heterogeneous. So far mutations in 15 genes have been identified in FA or FA-like patients (Cohen-Haguenauer *et al.,* 2006; Joenje *et al.,* 1987; Jonkers *et al.,* 2001; Lensch *et al.,* 1999; Stoepker *et al.,* 2011; Yamamoto *et al.,* 2011). The genes encoding the groups A (FANCA), B (FANCB), C (FANCC), D1 (FANCD1/BRCA2), D2 (FANCD2), E (FANCE), F (FANCF), G (FANCG), -I (FANCI/KIAA1794), J (FANCJ/ BRIP1), L (FANCL), M (FANCM), N (FANCN/PALB2), O/RAD51C and P/SLX4 proteins have been cloned (de Winter *et al.,* 1998, 2000a, 2000b; Howlett *et al.,* 2002; Joenje *et al.,* 2000; Letitus *et al.,* 2004; Levran *et al.,* 2005; Lo Ten Foe *et al.,* 1996; Meetei *et al.,* 2003, 2004, 2005; Meindl *et al.,* 2010; Reid *et al.,* 2006; Smogorzewska *et al.,* 2007; Somyajit *et al.,* 2010; Strathdee *et al.,* 1992; Timmers *et al.,* 2001; Xia *et al.,* 2006; Yamamoto *et al.,* 2011). The latter two genes are still thought of as tentative as they do not fall within a defined category biologically and the patients carrying these gene mutations are limited. The majority of mutations are found in *FANCA*, *FANCC* and *FANCC* genes in FA patients (Table 1). Recent studies on the biological function of these FA proteins have demonstrated that eight of the FA proteins (namely, FANCA, B, C, E, F, G, L, and M) form a nuclear multiprotein complex (Collins *et al.,* 2005; D'Andrea *et al.,* 2003; de Winter *et al.,* 2000; Meetei *et al.,* 2003; Smogorzewska *et al.,* 2007; Tischkowitz *et al.,* 2003; Walsh *et al.,* 1994), which functions as a nuclear E3 ubiquitin ligase that monoubiquitinates downstream FANCD2/FANCI dimer in response to DNA damage or DNA replication stress. This FANCD2/FANCI heterodimer then recruits other downstream FA proteins including FANCD1 (which is the breast cancer protein BRCA2), and the recently identified FANCJ, FANCN, FANCO and another breast cancer protein, BRCA1 (D'Andrea *et al.,* 2010), to nuclear loci containing damaged DNA and consequently influence important cellular processes such as DNA replication, cell-cycle control, and DNA damage repair. The core complex also interacts with the FAAP100 and FAPP24 proteins, which are also crucial components in the pathway (Ciccia *et al.,* 2007; Horejsi *et al.,* 2009; Collis *et al.,* 2008, Fig 1). FANCM and its interacting proteins, such as FAAP24 and MHF1, MHF2, also play a role in controlling the processing and stabilization of stalled replication

forks (Schwab *et al.,* 2010; Luke-Glaser *et al.,* 2010; Singh *et al.,* 2010).

**1. Introduction** 

*Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio* 

