KAP-1 promotes resection of broken DNA ends not protected by γ-H2AX and 53BP1 in G1-phase lymphocytes

Anthony T. Tubbs, Yair Dorsett, Elizabeth Chan, Beth Helmink, Baeck Seung Lee, Putzer Hung, Rosmy George, Andrea L. Bredemeyer, Anuradha Mittal, Rohit V. Pappu, Dipanjan Chowdhury, Nima Mosammaparast, Michael S. Krangel, Barry P. Sleckmana

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The resection of broken DNA ends is required for DNA double-strand break (DSB) repair by homologous recombination (HR) but can inhibit normal repair by nonhomologous end joining (NHEJ), the main DSB repair pathway in G1-phase cells. Antigen receptor gene assembly proceeds through DNA DSB intermediates generated in G1-phase lymphocytes by the RAG endonuclease. These DSBs activate ATM, which phosphorylates H2AX, forming γ-H2AX in flanking chromatin. γ-H2AX prevents CtIP from initiating resection of RAG DSBs. Whether there are additional proteins required to promote resection of these DNA ends is not known. KRAB-associated protein 1 (KAP-1) (TRIM28) is a transcriptional repressor that modulates chromatin structure and has been implicated in the repair of DNA DSBs in heterochromatin. Here, we show that in murine G1-phase lymphocytes, KAP-1 promotes resection of DSBs that are not protected by H2AX and its downstream effector 53BP1. In these murine cells, KAP-1 activity in DNA end resection is attenuated by a single-amino-acid change that reflects a KAP-1 polymorphism between primates and other mammalian species. These findings establish KAP-1 as a component of the machinery that can resect DNA ends in G1-phase cells and suggest that there may be species-specific features to this activity.

Original languageEnglish
Pages (from-to)2811-2821
Number of pages11
JournalMolecular and cellular biology
Volume34
Issue number15
DOIs
StatePublished - 2014

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    Tubbs, A. T., Dorsett, Y., Chan, E., Helmink, B., Lee, B. S., Hung, P., George, R., Bredemeyer, A. L., Mittal, A., Pappu, R. V., Chowdhury, D., Mosammaparast, N., Krangel, M. S., & Sleckmana, B. P. (2014). KAP-1 promotes resection of broken DNA ends not protected by γ-H2AX and 53BP1 in G1-phase lymphocytes. Molecular and cellular biology, 34(15), 2811-2821. https://doi.org/10.1128/MCB.00441-14