TY - JOUR TI - Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism AU - Rudolph, Johannes AU - Mahadevan, Jyothi AU - Dyer, Pamela AU - Luger, Karolin A2 - Heyer, Wolf-Dietrich A2 - Kuriyan, John VL - 7 PY - 2018 DA - 2018/08/08 SP - e37818 C1 - eLife 2018;7:e37818 DO - 10.7554/eLife.37818 UR - https://doi.org/10.7554/eLife.37818 AB - Poly(ADP-ribose) polymerase 1 (PARP1) is both a first responder to DNA damage and a chromatin architectural protein. How PARP1 rapidly finds DNA damage sites in the context of a nucleus filled with undamaged DNA, to which it also binds, is an unresolved question. Here, we show that PARP1 association with DNA is diffusion-limited, and release of PARP1 from DNA is promoted by binding of an additional DNA molecule that facilitates a ‘monkey bar’ mechanism, also known as intersegment transfer. The WGR-domain of PARP1 is essential to this mechanism, and a point mutation (W589A) recapitulates the altered kinetics of the domain deletion. Demonstrating the physiological importance of the monkey bar mechanism for PARP1 function, the W589A mutant accumulates at sites of DNA damage more slowly following laser micro-irradiation than wild-type PARP1. Clinically relevant inhibitors of PARP1 did not alter the rate or mechanism of the release of PARP1 from DNA. KW - protein DNA interaction KW - stopped flow kinetics KW - DNA damage KW - PARP1 KW - DNA repair JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -