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Sci Adv. 2017 May 24;3(5):e1601898. doi: 10.1126/sciadv.1601898. eCollection 2017 May.

CTCF facilitates DNA double-strand break repair by enhancing homologous recombination repair.

Author information

1
Departments of Oncology and Experimental Medicine, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, 3755 Chemin Côte-Ste-Catherine, Montréal, Quebec H3T 1E2, Canada.
2
Department of Microbiology and Immunology, McGill University, 3775 University Street, Montréal, Quebec H3A 2B4, Canada.
3
Department of Radiation Oncology, Medical Physics Unit, Jewish General Hospital, McGill University, Montréal, Quebec H3T 1E2, Canada.
4
Department of Oncology, Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montréal, Quebec H3A 1A3, Canada.

Abstract

The repair of DNA double-strand breaks (DSBs) is mediated via two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR) repair. DSB repair is vital for cell survival, genome stability, and tumor suppression. In contrast to NHEJ, HR relies on extensive homology and templated DNA synthesis to restore the sequence surrounding the break site. We report a new role for the multifunctional protein CCCTC-binding factor (CTCF) in facilitating HR-mediated DSB repair. CTCF is recruited to DSB through its zinc finger domain independently of poly(ADP-ribose) polymers, known as PARylation, catalyzed by poly(ADP-ribose) polymerase 1 (PARP-1). CTCF ensures proper DSB repair kinetics in response to γ-irradiation, and the loss of CTCF compromises HR-mediated repair. Consistent with its role in HR, loss of CTCF results in hypersensitivity to DNA damage, inducing agents and inhibitors of PARP. Mechanistically, CTCF acts downstream of BRCA1 in the HR pathway and associates with BRCA2 in a PARylation-dependent manner, enhancing BRCA2 recruitment to DSB. In contrast, CTCF does not influence the recruitment of the NHEJ protein 53BP1 or LIGIV to DSB. Together, our findings establish for the first time that CTCF is an important regulator of the HR pathway.

KEYWORDS:

BRCA2; CTCF; DNA damage; Homologous Recombination; PARP inhibitors; poly ADP ribosylation

PMID:
28560323
PMCID:
PMC5443639
DOI:
10.1126/sciadv.1601898
[Indexed for MEDLINE]
Free PMC Article

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