我院2013学年秋季学期系列学术讲座之四
题目：Oxidative Genome Damage and Repair: Ubiquity, Complexity and Pathological Implications
报告人：Sankar Mitra
Professor, Department of Biochemistry & Molecular Biology,
Radiation Oncology and, Sealy Center for Molecular Medicine,
The University of Texas Medical Branch Galveston, Texas
时间：2013年10月18日（周五），下午13:00-14:30 PM
地点：新葡萄8883官网AMG一楼邓祐才报告厅
Ubiquitous reactive oxygen species (ROS), continuously generated in the mitochondria, cytosol and nucleus of mammalian cells induce multitude of oxidized bases and single-strand breaks (SSBs) in the genome which are repaired via the base excision/SSB repair (BER/SSBR) pathway in all organisms. While the basic pathway comprising 4-5 sequential steps is evolutionarily conserved, the repair process and its regulation are highly complex in the mammals. Some general principles underlying repair of oxidized bases and ROS-induced SSBs have emerged from cumulative observations during last several years, summarized as follows.
1. Multiple sub-pathways carry out repair coordinated with transcription or replication using non-canonical proteins. The back-up function of multiple DNA glycosylases (DGs) acting as “relief pitchers” may explain the lack of phenotype of single deficiency of these enzymes.
2. BER proteins could exist as repair competent complexes which are stabilized via pairwise interactions among most components including direct, DNA-independent interaction between the first and the last enzymes in the pathway.
3. The complexes are dynamic and specific for each sub-pathway whose levels are increased by oxidative stress.
4. DGs initiating BER may act as “cow catchers” in preventing transcription or replication of oxidized bases which unlike bulky adducts do not inhibit these processes.
5. DGs and SSBR-initiating enzymes often contain disordered terminal segments that are non-conserved and dispensable for activity in vitro but provide the interface for interaction with other repair proteins to enhance repair efficiency.
6. Several RNA binding (hnRNP) proteins participate in BER/SSBR with distinct mechanisms. HnRNP-U in addition to providing specificity in transcription-coupled BER, serves as a molecular switch in temporally controlling repair of clustered damages. Explicit DSBs are repaired prior to repair of bi-stranded oxidized bases which could produce additional DSB intermediates. Ku-independent, alternative end joining (Alt-EJ) requiring SSBR proteins is likely to repair these secondary DSBs. Other hnRNPs, TDP-43 and FUS, etiologically linked to neurodegenerative diseases, appear to be involved in repair of DSBs in neuronal cells.
7. Transition metal ions (Fe/Cu) accumulating in neurodegenerative brains act as double-edged swords by inducing ROS and preventing oxidative base damage repair.
8. Finally, TET oxidases and histone demethylases generate ROS during oxidative demethylation of meCpG and meLys/meArg during transcriptional activation leading to promoter/enhancer-specific oxidized bases/SSBs which need to be repaired prior to transcription initiation.
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