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实验室

11:00-12:00, Friday, June 8 ,2018


Speaker: Xiaolan Zhao, Ph.D.

Professor,

Member & Laboratory Head, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center    

Topic:   SUMO and Smc5/6-based regulation of recombination during replication

Host:    Li-Lin Du ,Ph.D.

Abstract

Homologous recombination has a broad influence on genome maintenance and human disease. Both the formation of recombination intermediates, such as Holliday junctions and D-loops, and their processing into liner products are intricately regulated. This regulation is crucial because untimely formation of recombination intermediates in some cellular contexts and inefficeint prcoessing of recombination intermediates in general result in DNA non-disjunction in mitosis and subsequent DNA fragility. Our previous work in yeast suggested an important role for the Smc5/6 complex in limiting the DNA helicase Mph1-mediated generation of recombination intermediates at stalled replication forks under DNA damage conditions. Our recent work further show that this regulation applies to situations when replication forks are stalled by programmed protein barriers within the highly repetitive rDNA locus under normal growth conditions. Thus, a general principle is that Smc5/6 limits Mph1-mediated recombination when forks are stalled either by template lesions or protein barriers. We further demonstrated that this regulation accounts for the primary function of Smc5/6 during mitotic growth. In parallel, we and others have found that Smc5/6 also promotes recombination intermediate removal via SUMO-based regulation of the Sgs1 helicase required for Holiday junction dissolution. These findings suggest a dual role of Smc5/6 at early and late stages of recombination by regulating two DNA helicase in different manners, and these forms of regulation work together to prevent recombination intermediate accumulation and the resultant DNA fragility. These findings have potential clinical implications as DNA damage syndromes caused by Smc5/6 complex deficiency exhibit DNA nondisjunction and DNA fragility.