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DNA Repair (Amst). 2014 Apr;16:11-22. doi: 10.1016/j.dnarep.2014.01.010. Epub 2014 Feb 20.

Functional overlaps between XLF and the ATM-dependent DNA double strand break response.

Author information

1
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02115, United States.
2
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02115, United States. Electronic address: alt@enders.tch.harvard.edu.
3
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02115, United States. Electronic address: oksenych@gmail.com.

Abstract

Developing B and T lymphocytes generate programmed DNA double strand breaks (DSBs) during the V(D)J recombination process that assembles exons that encode the antigen-binding variable regions of antibodies. In addition, mature B lymphocytes generate programmed DSBs during the immunoglobulin heavy chain (IgH) class switch recombination (CSR) process that allows expression of different antibody heavy chain constant regions that provide different effector functions. During both V(D)J recombination and CSR, DSB intermediates are sensed by the ATM-dependent DSB response (DSBR) pathway, which also contributes to their joining via classical non-homologous end-joining (C-NHEJ). The precise nature of the interplay between the DSBR and C-NHEJ pathways in the context of DSB repair via C-NHEJ remains under investigation. Recent studies have shown that the XLF C-NHEJ factor has functional redundancy with several members of the ATM-dependent DSBR pathway in C-NHEJ, highlighting unappreciated major roles for both XLF as well as the DSBR in V(D)J recombination, CSR and C-NHEJ in general. In this review, we discuss current knowledge of the mechanisms that contribute to the repair of DSBs generated during B lymphocyte development and activation with a focus on potential functionally redundant roles of XLF and ATM-dependent DSBR factors.

KEYWORDS:

53BP1; ATM; Cernunnos; DNA-PKcs; NHEJ; V(D)J recombination

PMID:
24674624
PMCID:
PMC4017585
DOI:
10.1016/j.dnarep.2014.01.010
[Indexed for MEDLINE]
Free PMC Article

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