53BP1 regulates DSB repair using Rif1 to control 5’ end resection
By Michal Zimmermann, Francisca Lottersberger, S. B. Buonomo, Agnel Sfeir, T. de Lange. Science, 2013
615 citations recorded by the source corpus.
Fixing Broken DNA Some physiological processes, such as immunoglobulin class switching and telomere attrition, result in double-stranded DNA breaks. The DNA damage repair protein, 53BP1, prevents nucleolytic processing of these breaks, but the proteins it partners with to do this are unknown (see the Perspective by Lukas and Lukas). Di Virgilio et al. (p. 711, published online 10 January), using mass spectroscopy–based methods, and Zimmermann et al. (p. 700, published online 10 January), using a telomere-based assay, identify Rif1 as a 53BP1 phosphorylation- and DNA damage–dependent interaction partner. Mice with a B cell–specific deletion in Rif1 showed impaired immunoglobulin class switching. Rif1-deficient cells exhibited extensive 5′-3′ resection at DNA ends, with enhanced genetic instability. Thus, Rif1 partners with 53BP1 to promote the proper repair of double-stranded DNA breaks. In mammalian cells, Rap1-interacting factor 1 protects DNA ends against resection. [Also see Perspective by Lukas and Lukas] The choice between double-strand break (DSB) repair by either homology-directed repair (HDR) or nonhomologous end joining (NHEJ) is tightly regulated. Defects in this regulation can induce genome instability and cancer. 53BP1 is critical for the control of DSB repair, promoting NHEJ, and inhibiting the 5′ end resection needed for HDR. Using dysfunctional telomeres and genome-wide DSBs, we identify Rif1 as the main factor used by 53BP1 to impair 5′ end resection. Rif1 inhibits resection involving CtIP, BLM, and Exo1; limits accumulation of BRCA1/BARD1 complexes at sites of DNA damage; and defines one of the mechanisms by which 53BP1 causes chromosomal abnormalities in Brca1-deficient cells. These data establish Rif1 as an important contributor to the control of DSB repair by 53BP1.
Subfields: Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/3fcf4d5fe25e25097aae6f5175db31352cf7f79c
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In Molecular Biology
Citations in the corpus
- Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “2013) and also involves RIF1, which binds ATM-phosphorylated 53BP1 (Chapman et al. 2013; Escribano-Diaz et al. 2013; Feng et al. 2013; Zimmermann et al. 2013).”
- Repair of strand breaks by homologous recombination. (2013, background): “Several laboratories have recently described the RIF1 protein as an effector of DNA end resection control by 53BP1 (Chapman et al. 2013; Di Virgilio et al. 2013; EscribanoDiaz et al. 2013; Feng et al. 2013; Zimmermann et al. 2013).”
- 53BP1 is a reader of the DNA damage-induced H2A Lys15 ubiquitin mark (2013, positive): “Class switching to IgG1 was assayed in 53BP1 murine primary B cells complemented with 53BP1 (1-1711) and mutants thereof by retroviral delivery.”