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The Role of FBH1 in Maintenance of Genome Stability
Šimandlová, Jitka ; chevelev, Igor (advisor) ; Kratochvíl, Lukáš (referee)
The genome is constantly threatened by various damaging agents and maintaining its integrity is crucial for all organisms. Several repair pathways have been implicated in the removal of different types of lesions from DNA. Among them, homologous recombination (HR) plays a key role in repair of double-strand breaks. HR is a highly important repair mechanism which has to be tightly regulated to prevent excessive HR events. These events could interfere with other DNA repair pathways, generate toxic intermediates, or block the progression of the replication fork. Therefore, it is not surprising that cells have evolved mechanisms that counteract inappropriate HR events. As it has been shown recently, cells possess DNA helicases capable of preventing excessive recombination. A novel human DNA helicase, hFBH1, belonging to the superfamily I has been shown to function as pro- and anti- recombinase. Similar to the two members of RecQ family, BLM and RECQL5, FBH1 disrupts Rad51 from nucleofilament. However, FBH1 might also promote initiation of HR. The FBH1 helicase possesses additional high conserved F-box motif which allows it to act within a Skp1-Cullin-F-box, SCF, complex as ubiquitin ligase and target proteins for degradation.
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Characterization of Antirecombinase Activity of Human FBH1 Helicase
Šimandlová, Jitka ; Janščák, Pavel (advisor) ; Cséfalvay, Eva (referee)
Homologous recombination (HR) is an essential mechanism for accurate repair of DNA double-strand breaks (DSBs). However, HR must be tightly controlled because excessive or unwanted HR events can lead to genome instability, which is a prerequisite for premature aging and cancer development. A critical step of HR is the loading of RAD51 molecules onto single-stranded DNA regions generated in the vicinity of the DSB, leading to the formation of a nucleoprotein filament. Several DNA helicases have been involved in the regulation of the HR process. One of these is human FBH1 (F-box DNA helicase 1) that is a member of SF1 superfamily of helicases. As a unique DNA helicase, FBH1 additionally possesses a conserved F-box motif that allows it to assemble into an SCF complex, an E3 ubiquitin ligase that targets proteins for degradation. FBH1 has been implicated in the restriction of nucleoprotein filament stability. However, the exact mechanism of how FBH1 controls the RAD51 action is still not certain. In this work, we revealed that FBH1 actively disassembles RAD51 nucleoprotein filament. We also show that FBH1 interacts with RAD51 and RPA physically in vitro. Based on these data, we propose a potential mechanism of FBH1 antirecombinase function.
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The Role of FBH1 in Maintenance of Genome Stability
Šimandlová, Jitka ; Kratochvíl, Lukáš (referee) ; chevelev, Igor (advisor)
The genome is constantly threatened by various damaging agents and maintaining its integrity is crucial for all organisms. Several repair pathways have been implicated in the removal of different types of lesions from DNA. Among them, homologous recombination (HR) plays a key role in repair of double-strand breaks. HR is a highly important repair mechanism which has to be tightly regulated to prevent excessive HR events. These events could interfere with other DNA repair pathways, generate toxic intermediates, or block the progression of the replication fork. Therefore, it is not surprising that cells have evolved mechanisms that counteract inappropriate HR events. As it has been shown recently, cells possess DNA helicases capable of preventing excessive recombination. A novel human DNA helicase, hFBH1, belonging to the superfamily I has been shown to function as pro- and anti- recombinase. Similar to the two members of RecQ family, BLM and RECQL5, FBH1 disrupts Rad51 from nucleofilament. However, FBH1 might also promote initiation of HR. The FBH1 helicase possesses additional high conserved F-box motif which allows it to act within a Skp1-Cullin-F-box, SCF, complex as ubiquitin ligase and target proteins for degradation.
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