POLD2 Promotes Chromosomal Rearrangements and Inaccurate End-Joining in Human Cells

Abstract

Chromosomal translocations are recurrent genetic rearrangements with the potential to initiate carcinogenesis. While, the clinical etiology of chromosomal translocations is well established, the mechanisms responsible for translocations in mammalian cells are poorly understood. Here, we show that POLD2, a structural subunit of DNA polymerase δ (Pol δ) and DNA polymerase ζ (Pol ζ), is a translocation-promoting factor and its depletion does not affect cell cycle distribution, endonuclease cutting efficiency, or expression of canonical DSB repair genes. Furthermore, we show that POLD2 is recruited to DSBs and promotes inaccurate end joining at translocations and DSBs joined locally. Finally, POLD2 promotes both microhomology-mediated end joining and homology directed repair as measured using fluorescent reporters. We hypothesize that POLD2 stabilizes DSB ends tethered by microhomology, by catalyzing DNA synthesis across the break via Pol δ or Pol ζ. These results highlight previously unappreciated roles for Pol δ and Pol ζ in DSB repair.