Tens of thousands of DNA single-strand breaks (SSBs) arise spontaneously every day from various sources including abortive topoisomerase 1 (Top1) activity and oxidative stress. It is therefore critical that we understand both the mechanisms employed by cells to repair these breaks and the impact of unrepaired SSBs on cell fate and human disease. This is highlighted by the association of a mutation of the 3’-DNA processing enzyme tyrosyl DNA phosphodiesterase (TDP1) that repairs stalled DNA toposiomerase1 and the human neurological disorder Spinocerebellar ataxia with axonal neuropathy (SCAN1). Despite this important catalytic function fulfilled by TDP1, it remains together with the newly identified enzyme TDP2 the only human enzymes that display this catalytic activity. Here, we employ a combination of yeast genetics, molecular, cellular, and whole animal approaches to unravel novel mechanisms for the repair of this type of DNA lesion and determine the impact of loss of these mechanisms on neuronal viability. This will further our understanding of the pathological and aging-related neurological demise and is expected to serve as a platform for the development of safer and perhaps more efficient strategies to delay or prevent neurological dysfunction. 

Alagoz, Meryem, Chiang, Shih-Chieh, Sharma, Abhishek and El-Khamisy, Sherif F (2013) ATM deficiency results in accumulation of DNA-Topoisomerase I covalent intermediates in neural cells. PLoS ONE, 8 (4). e58239. ISSN 1932-6203

Hudson, J J, Chiang, S C, Wells , O S, Rookyard, C and El-Khamisy, S (2012) SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair. Nature Communications, 3. p. 733. ISSN 2041-1723

Zeng, Z, Sharma, A, Ju, L, Murai, J, Umans, L, Vermeire, L, Pommier, Y, Takeda, S, Huylebroeck, D, Caldecott, K and El-Khamisy, S (2012) TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1. Nucleic Acids Research, 40 (17). pp. 8371-8380. ISSN 1362-4962

El-Khamisy, Sherif (2011) To live or to die: a matter of processing damaged DNA termini in neurons. EMBO Molecular Medicine, 3 (2). pp. 78-88. ISSN 17574676

Zeng, Zhihong, Cortes-Ledesma, Felipe, El-Khamisy, Sherif and Caldecott, Keith W (2010) TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. Journal of Biological Chemistry, 286 (1). pp. 403-409. ISSN 0021-9258

El-Khamisy, Sherif, Chiang, Shih-Chieh and Carroll, John (2010) TDP1 serine 81 promotes interaction with DNA ligase IIIalpha and facilitates cell survival following DNA damage. Cell Cycle, 9 (3). pp. 588-595. ISSN 15384101

Cortes Ledesma, Felipe, El-Khamisy, Sherif F, Zuma, Maria C, Osborn, Kay and Caldecott, Keith W (2009) A human 5'-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature, 461 (7264). pp. 674-678. ISSN 0028-0836

Lee, Youngsoo, Katyal, Sachin, Li, Yang, El-Khamisy, Sherif F, Russell, Helen R, Caldecott, Keith W and McKinnon, Peter J (2009) The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1. Nature Neuroscience, 12 (8). 973-U35. ISSN 1097-6256

El-Khamisy, Sherif F, Katyal, Sachin, Patel, Poorvi, Ju, Limei, McKinnon, Peter J and Caldecott, Keith W (2009) Synergistic decrease of DNA single-strand break repair rates in mouse neural cells lacking both Tdp1 and aprataxin. DNA Repair, 8 (6). pp. 760-766. ISSN 1568-7864

Reynolds, John J, El-Khamisy, Sherif F, Katyal, Sachin, Clements, Peter, McKinnon, Peter J and Caldecott, Keith W (2009) Defective DNA ligation during short-patch single-strand break repair in ataxia oculomotor apraxia 1. Molecular and Cellular Biology, 29 (5). pp. 1354-1362. ISSN 0270-7306

Reynolds, John J, El-Khamisy, Sherif F and Caldecott, Keith W (2009) Short-patch single-strand break repair in ataxia oculomotor apraxia-1. In: Symposium on DNA Damage - From Causes to Cures Univ Cambridge, Robinson Coll, Cambridge, ENGLAND, DEC 15-17, 2008, Cambridge, ENGLAND.

El-Khamisy, S F and Caldecott, K W (2007) DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1. Neuroscience, 145 (4). pp. 1260-1266. ISSN 0306-4522