报告题目：The Roads to Death, Uncovering DNA damage response pathways by C. elegans genetics

报告人：Anton Gartner教授
　　　　The University of Dundee，United Kingdom

时间：2009年10月12日上午10:00－11:30

地点：遗传发育所一号楼B210

实验室主页：http://www.lifesci.dundee.ac.uk/groups/anton_gartner/

摘要：

Coordination of DNA repair with cell cycle progression and apoptosis is a central task of the DNA damage response machinery. A key intermediate of recombinational repair and meiotic recombination, first proposed by Robin Holliday in 1964, are four-way DNA intermediates. These intermediates have to be resolved to allow for proper chromosome segregation. Enzymes that resolve Holliday junctions by symmetric endonucleolytic cleavage have been isolated from bacteriophages, bacteria and archaea, and have been found in yeast mitochondria. Although nuclear Holliday junction resolvase activities had been measured for almost twenty years, the corresponding Holliday Junction resolving enzyme(s) have remained elusive. The biochemical purification of a Holliday Junction resolvase activity was recently reported, and resolvase activity was linked to GEN1, although the in vivo functions of GEN1 remained unclear 1).

Using an independent unbiased genetic screening approach aimed at identifying genes involved in DNA double strand break repair and DNA damage response signalling, followed by a positional mapping we identified several alleles of C. elegans gen-1. We find that GEN-1 is required for recombinational repair in response to DNA double strand breaks, but is not necessary for processing other forms of DNA damage. In addition, GEN-1 is not required for meiotic recombination. Importantly, the C-terminus of GEN-1 plays a role in DNA damage signalling to affect germ cell cycle arrest and germ cell apoptosis that is separable from its role in DNA repair. Our biochemical analysis suggests that GEN-1 Holiday Junction resolvase activity may be required for DNA repair but may be dispensable for DNA damage signalling. The DNA damage signalling function of GEN-1 defines a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, ATM/ATR and cep-1/p53 activation. Furthermore, we show that GEN-1 is needed in conjunction with the 9-1-1 DNA repair complex to ensure survival even in the absence of DNA damaging agents. Our results point towards the intriguing possibility that a dual function Holliday junction resolvase may coordinate DNA damage signalling with a terminal step in DNA double strand break repair. The dual function of a Holliday Junction resolving enzyme in DNA damage signalling is entirely unexpected.

近期发表主要文章：

B. Schumacher, M. Hanazawa, MH. Lee, S. Nayak, K. Volkmann; R. Hofmann, M. Hengartner, T. Schedl and A. Gartner (2005). Translational Repression of C. elegans p53 by GLD-1 regulates DNA damage induced apoptosis. Cell 120: 357-368

S. Greiss, B. Schumacher, K. Grandien, J. Rothblatt, A. Gartner. (2008). Transcriptional profiling in C. elegans suggests DNA damage dependent apoptosis as an ancient function of the p53 family. BMC Genomics. Jul 15; 9: 334.

A. Gartner, PR. Boag and TK. Blackwell (2008). Germline Survival and Apoptosis, WormBook, ed. The C. elegans Research Community. WormBook, Sept; 1-20

S. Greiss, J. Hall, S. Ahmed, A. Gartner. (2008). C. elegans SIR-2.1 translocation is linked to a pro-apoptotic pathway parallel to cep-1/p53-like during DNA damage induced apoptosis. Genes & Development, Oct, 22(20): 2831-41.

S. Moser, S. von Elsner, I. Buessing, A. Alpi, R. Schnabel, A. Gartner. (2009). Functional Dissection of C. elegans CLK2/TEL2 cell cycle defects during embryogenesis and germ line development. PLOS Genetics, Apr, 5; 4: