Fanconi anemia (FA) is a rare genetic disorder characterized by developmental abnormalities, progressive aplastic anemia, and increased cancer incidence. Although FA pathway is believed to participate in DNA repair, the exact role of this pathway in DNA repair remains to be elucidated. The key function of the FA pathway is to promote FANCD2 monoubiquitination following DNA damage. However, how FANCD2 is recruited to sites of DNA damage is unknown. More importantly, the task of FANCD2 monoubiquitination in DNA repair is still a mystery. We made two discoveries recently, which will likely answer the questions mentioned above. First, when we were studying the newly identified SOSS complexes in DNA repair, we found that these complexes also associated with FANCI and FANCD2. Moreover, we showed that SOSS complexes are required for the efficient chromatin loading, focus formation, and monoubiquitination of FANCI and FANCD2 following DNA damage. These studies suggest that SOSS complexes act together with the FA core complex and participate in the regulation of FANCI/FANCD2 ubiquitination following DNA damage. Second, we discovered that an ubiquitin-binding zinc finger (UBZ) domain-containing nuclease KIAA1018/FAN1 interacted with FANCD2. Our subsequent studies suggested that this protein acts downstream of FANCD2 and participates in DNA repair. We propose that this protein links the FA pathway to DNA damage repair. Moreover, we are also studying another newly identified FA protein SLX4/FANCP, which may act with KIAA1018/FAN1 in DNA repair. Based on these exciting preliminary studies, we propose to: 1) Define the regulation of FANCI/FANCD2 localization via their associations with SOSS complexes;2) Determine the functional significance of KIAA1018/FAN1 and SLX4/FANCP in DNA repair;3) Identify the in vivo functions of KIAA1018/FAN1 in the maintenance of genomic stability and tumor suppression.

Public Health Relevance

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, developmental abnormalities and high incidence of malignancies. There are at least 15 genes involved in the FA pathway, which are believed to function in DNA damage repair;however, the most critical event in the FA pathway is monoubiquitination of FANCD2. Further study of the regulation and function of FANCD2 monoubiquitination will reveal how cells promote survival and ensure genomic stability following DNA damage, which are critically important for understanding the efficacy of cancer treatments with radiation and chemotherapeutic agents.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Radiation Therapeutics and Biology Study Section (RTB)
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Pelroy, Richard
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University of Texas MD Anderson Cancer Center
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Tian, Yanyan; Shen, Xi; Wang, Rui et al. (2017) Constitutive role of the Fanconi anemia D2 gene in the replication stress response. J Biol Chem 292:20184-20195
Lee, Yuan-Cho; Zhou, Qing; Chen, Junjie et al. (2016) RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response. Curr Biol 26:3257-3268
Tian, Yanyan; Paramasivam, Manikandan; Ghosal, Gargi et al. (2015) UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold. Cell Rep 10:1957-66
Huang, Yaling; Leung, Justin W C; Lowery, Megan et al. (2014) Modularized functions of the Fanconi anemia core complex. Cell Rep 7:1849-57