SMC 5/6 acts jointly with Fanconi anemia factors to support DNA repair and genome stability

Abstract

SMC 5/6 function in genome integrity remains elusive. Here, we show that SMC 5 dysfunction in avian DT 40 B cells causes mitotic delay and hypersensitivity toward DNA intra‐ and inter‐strand crosslinkers ( ICL s), with smc5 mutants being epistatic to FANCC and FANCM mutations affecting the Fanconi anemia ( FA ) pathway. Mutations in the checkpoint clamp loader RAD 17 and the DNA helicase DDX 11, acting in an FA ‐like pathway, do not aggravate the damage sensitivity caused by SMC 5 dysfunction in DT 40 cells. SMC 5/6 knockdown in HeLa cells causes MMC sensitivity, increases nuclear bridges, micronuclei, and mitotic catastrophes in a manner similar and non‐additive to FANCD 2 knockdown. In both DT 40 and HeLa systems, SMC 5/6 deficiency does not affect FANCD 2 ubiquitylation and, unlike FANCD 2 depletion, RAD 51 focus formation. SMC 5/6 components further physically interact with FANCD 2‐I in human cells. Altogether, our data suggest that SMC 5/6 functions jointly with the FA pathway to support genome integrity and DNA repair and may be implicated in FA or FA ‐related human disorders. image The structural maintenance complex SMC 5/6 interacts with and functions jointly with key components of the Fanconi anemia pathway to facilitate DNA repair and preserve genome stability. SMC 5/6 dysfunction causes mitotic delays and DNA damage sensitivity. SMC 5/6 functions jointly with FA components and FA ‐like pathways in DNA repair. SMC 5/6 acts jointly with FANCD 2 to prevent micronuclei and mitotic aberrations. SMC 5/6 interacts with FANCD 2‐I without affecting FANCD 2‐I ubiquitylation.