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[2014 Fall Life Sciences & IBB Regular Seminar]
▶Subject: Modulation of Multiple DNA Repair Pathways by Fanconi Anemia Protein SLX4/FANCP
▶Speaker: Prof. Yonghwan Kim (Department of Life Systems, Sookmyung Women’s University)
▶Place: Auditorium(1F), Postech Biotech Center
Fanconi anemia is a rare recessive disorder characterized by genome instability, congenital malformations, progressive bone marrow failure and predisposition to hematologic malignancies and solid tumors. We identified biallelic SLX4 mutations in two individuals with typical clinical features of Fanconi anemia. In further studies, we found that SLX4/FANCP modulates multiple DNA repair pathways by providing specific nucleases in different types of DNA damage. Holliday junctions, the DNA intermediates of homologous recombination need to be faithfully processed in order to preserve genome integrity. In human cells the BLM helicase complex promotes non-nucleolytic dissolution of double Holliday junctions. In vitro, Holliday junctions may be nucleolytically processed by MUS81-EME1, GEN1, and SLX4-SLX1. Here, we take advantage of SLX4-null cells to dissect the requirements for each of these proteins during Holliday junction resolution in vivo, and demonstrate an important role for SLX4 dependent complexes in human cells. We show that SLX4-associated MUS81-EME1 and SLX1 work as an in vivo HJ resolvase, which acts in an alternate pathway to BLM-directed HJ dissolution. If neither of these pathways is present, the cells are inviable due to mitotic dysfunction resulting from the inability to segregate their chromosomes. In this setting, GEN1, although active in the cells, cannot substitute for the activity of the SLX4-associated nucleases. Even in the presence of BLM, one of the Holliday junction resolvase activities associated with SLX4 or GEN1 is still required for cell viability. These data indicate that the BLM complex is unable to process all homologous recombination intermediates arising during DNA replication and that nucleolytic Holliday junction resolution is essential in human cells.
▶Inquiry: Prof. Cho, Yunje (279-2288)
* This seminar will be given in English