PT  - JOURNAL ARTICLE
AU  - Rajashree A. Deshpande
AU  - Logan R. Myler
AU  - Michael M. Soniat
AU  - Nodar Makharashvili
AU  - Linda Lee
AU  - Susan P. Lees-Miller
AU  - Ilya J. Finkelstein
AU  - Tanya T. Paull
TI  - DNA-PKcs promotes DNA end processing
AID  - 10.1101/395731
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 395731
4099  - http://biorxiv.org/content/early/2018/09/06/395731.short
4100  - http://biorxiv.org/content/early/2018/09/06/395731.full
AB  - DNA-dependent Protein Kinase (DNA-PK) coordinates the repair of double-strand breaks through non-homologous end joining, the dominant repair pathway in mammalian cells. Breaks can also be resolved through homologous recombination during S/G2 cell cycle phases, initiated by the Mre11-Rad50-Nbs1 (MRN) complex and CtIP-mediated resection of 5’ strands. The functions of DNA-PK are considered to be end-joining specific, but here we demonstrate that human DNA-PK also plays an important role in the processing of DNA double-strand breaks. Using ensemble biochemistry and single-molecule approaches, we show that the MRN complex in cooperation with CtIP is stimulated by DNA-PK to perform efficient endonucleolytic processing of DNA ends in physiological conditions. This activity requires both CDK and ATR phosphorylation of CtIP. These unexpected results could explain the absence of DNA-PK deletion mutations in the human population, as homologous recombination is an essential process in mammals.One sentence summary An enzyme critical for non-homologous repair of DNA double-strand breaks also stimulates end processing for homologous recombination.