js33333金沙线路检测2017年度秋季学期学术系列讲座之四
题目：The DNA damage response: a matter of checks and balances
讲座人：Yosef  Shiloh，Ph.D.
Group leader， Professor, 
Department of Human Molecular Genetics and Biochemistry, 
Sackler School of Medicine, 
Tel Aviv University.
时间：2017年10月20日（星期五），13:00-14:30
地点：js33333金沙线路检测邓祐才报告厅 
主持人：孔道春
摘要：
Maintenance of genome stability is critical for cellular homeostasis and the organism’s health. The primary threat on to genome stability is DNA damage stemming from both endogenous and exogenous agents. DNA lesions activate the DNA damage response (DDR) - a complex signaling network consisting of DNA repair pathways and many other branches that profoundly modulate numerous cellular circuits. The DDR is vigorously activated by critical DNA lesions such as double strand breaks (DSBs). The breadth of this network is based on a core of DDR-dedicated proteins and temporary recruitment of hundreds of proteins from various cellular circuitries. The primary transducer of the DSB response – the serine-threonine kinase, ATM, which was identified in our lab – mobilizes this network by initiating a multi-level cascade of protein phosphorylations. Indeed, a major driving force and regulator of the DDR are protein post-translational modifications, in particular phosphorylation and ubiquitylation. For all its breadth and complexity, the DDR is highly structured and meticulously regulated. Several examples of this precise regulation will be described. For example, we recently found that following initial ubiquitylation of proteins at DSB sites – mediated largely by the E3 ubiquitin ligases, RNF8 and RNF168 – timely repair of the DSB will occur only after further tweaking by an E4 ubiquitin ligase. E4 ligases bind to a single conjugated ubiquitin or an oligoubiquitin chain, and extend and regulate the length of the chain. We discovered that the E4 ubiquitin ligase, UBE4A, is a crucial player in this process at DSB sites. It is recruited to damage sites, in a manner dependent on previous protein ubiquitylation, where it enhances and maintains K48- and K63-linked ubiquitin chains. This step is required for timely recruitment of other DDR players and proper spatial organization of the rapidly forming DSB-associated protein hubs. This pathway is also vital for the fine balance between the various DSB repair pathways. Our results add a critical regulatory level to the DSB response and underscore the importance of fine-tuning of this complex network for accurate and balanced execution of DSB repair.
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