53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility

Abstract

When either exogenous or endogenous double-strand breaks occur, the p53 binding protein 53BP1 is one of the earliest proteins to be recruited to the site of the break. 53BP1 helps to promote rejoining of DNA ends during class switch recombination; in a pair of papers in this week's Nature, the laboratories of André Nussenzweig and Titia de Lange show it is also required for V(D)J recombination and for joining of DNA breaks in telomeres. In V(D)J recombination, the ends of the programmed double-strand break are degraded when 53BP1 is absent, and joining between distal V and DJ segments is affected. At broken telomeres, 53BP1 increases the volume of the nucleus searched by the DNA ends so that they are more likely to encounter a partner to which they can be ligated. Thus, 53BP1 facilitates repair by changing the dynamics of movement of broken ends, making long-range interactions more frequent. 53BP1 is required for V(D)J recombination and for joining of DNA breaks in telomeres. In V(D)J recombination, the ends of the programmed double-strand break are degraded when 53BP1 is absent, and joining between distal V and DJ segments is affected. At broken telomeres, 53BP1 increases the mobility of the DNA ends in the nucleus so that they are more likely to encounter a partner to which they can be ligated. Thus, 53BP1 facilitates repair by changing the dynamics of movement of broken ends, making long-range interactions more frequent. Double-strand breaks activate the ataxia telangiectasia mutated (ATM) kinase, which promotes the accumulation of DNA damage factors in the chromatin surrounding the break. The functional significance of the resulting DNA damage foci is poorly understood. Here we show that 53BP1 (also known as TRP53BP1), a component of DNA damage foci, changes the dynamic behaviour of chromatin to promote DNA repair. We used conditional deletion of the shelterin component TRF2 (also known as TERF2) from mouse cells (TRF2fl/-) to deprotect telomeres, which, like double-strand breaks, activate the ATM kinase, accumulate 53BP1 and are processed by non-homologous end joining (NHEJ)1,2. Deletion of TRF2 from 53BP1-deficient cells established that NHEJ of dysfunctional telomeres is strongly dependent on the binding of 53BP1 to damaged chromosome ends. To address the mechanism by which 53BP1 promotes NHEJ, we used time-lapse microscopy to measure telomere dynamics before and after their deprotection. Imaging showed that deprotected telomeres are more mobile and sample larger territories within the nucleus. This change in chromatin dynamics was dependent on 53BP1 and ATM but did not require a functional NHEJ pathway. We propose that the binding of 53BP1 near DNA breaks changes the dynamic behaviour of the local chromatin, thereby facilitating NHEJ repair reactions that involve distant sites, including joining of dysfunctional telomeres and AID (also known as AICDA)-induced breaks in immunoglobulin class-switch recombination.