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53BP1 promotes microhomology-mediated end-joining in G1-phase cells.

Xiong X1, Du Z1, Wang Y1, Feng Z1, Fan P2, Yan C3, Willers H4, Zhang J5.

Nucleic Acids Res. 2015;43(3):1659-70.

1Department of Radiation Oncology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, BRB 323, Cleveland, OH 44106, USA.

2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine,1650 Orleans Street, Baltimore, MD 21231, USA.

3Department of Biochemistry and Molecular Biology, Georgia Regents University, 1410 Laney Walker Blvd., CN-2134, Augusta, GA 30912, USA.

4Department of Radiation Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.

5Department of Radiation Oncology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, BRB 323, Cleveland, OH 44106, USA [email protected]

 

Abstract

Alternative non-homologous end joining (alt-NHEJ) was originally identified as a backup repair mechanism in the absence of classical NHEJ (c-NHEJ) factors but recent studies have demonstrated that alt-NHEJ is active even when c-NHEJ as well as homologous recombination is available. The functions of 53BP1 in NHEJ processes are not well understood. Here, we report that 53BP1 promotes DNA double-strand break (DSB) repair and genomic stability not only in c-NHEJ-proficient but also -deficient human G1-phase cells. Using an array of repair substrates we show that these effects of 53BP1 are correlated with a promotion of microhomology-mediated end-joining (MMEJ), a subtype of alt-NHEJ, in G1-phase. Consistent with a specific role in MMEJ we confirm that 53BP1 status does not affect c-NHEJ. 53BP1 supports sequence deletion during MMEJ consistent with a putative role in facilitating end-resection. Interestingly, promotion of MMEJ by 53BP1 in G1-phase cells is only observed in the presence of functional BRCA1. Depletion of both 53BP1 and BRCA1 increases repair needing microhomology usage and augments loss of DNA sequence, suggesting that MMEJ is a highly regulated DSB repair process. Together, these findings significantly expand our understanding of the cell-cycle-dependent roles of 53BP1 in DSB repair.

© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

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