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Mol Cell Biol. 2014 Aug;34(15):2811-21. doi: 10.1128/MCB.00441-14. Epub 2014 May 19.

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

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
3
Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University, St. Louis, Missouri, USA.
4
Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA sleckman@immunology.wustl.edu.

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.

PMID:
24842905
PMCID:
PMC4135573
DOI:
10.1128/MCB.00441-14
[Indexed for MEDLINE]
Free PMC Article

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