Abstract
SMC5/6 function in genome integrity remains elusive. Here, we show that SMC5 dysfunction in avian DT40 B cells causes mitotic delay and hypersensitivity toward DNA intra‐ and inter‐strand crosslinkers (ICLs), with smc5 mutants being epistatic to FANCC and FANCM mutations affecting the Fanconi anemia (FA) pathway. Mutations in the checkpoint clamp loader RAD17 and the DNA helicase DDX11, acting in an FA‐like pathway, do not aggravate the damage sensitivity caused by SMC5 dysfunction in DT40 cells. SMC5/6 knockdown in HeLa cells causes MMC sensitivity, increases nuclear bridges, micronuclei, and mitotic catastrophes in a manner similar and non‐additive to FANCD2 knockdown. In both DT40 and HeLa systems, SMC5/6 deficiency does not affect FANCD2 ubiquitylation and, unlike FANCD2 depletion, RAD51 focus formation. SMC5/6 components further physically interact with FANCD2‐I in human cells. Altogether, our data suggest that SMC5/6 functions jointly with the FA pathway to support genome integrity and DNA repair and may be implicated in FA or FA‐related human disorders.
Highlights
Genomic integrity is safeguarded by multiple genome caretakers that are often implicated in chromosome metabolism reactions induced by various types of replication stress
As SMC5 is present on chromosome Z, with only one replacement we generated SMC5/3AID6FLAG cells expressing TIR1 cells
We investigated potential genetic relationships between SMC5 and FANCC, which is essential for FANCD2-I ubiquitylation and required for both homologous recombination (HR) and TLS-mediated pathways of DNA repair in DT40 cells [44]
Summary
Genomic integrity is safeguarded by multiple genome caretakers that are often implicated in chromosome metabolism reactions induced by various types of replication stress. The structural maintenance of chromosomes (SMC) complexes, including cohesin (SMC1/3), condensin (SMC2/4), and SMC5/6, are critical for chromosome transactions that ensure normal proliferation and genome integrity. SMC complexes form molecular rings that can entrap genomic DNA [1]. The SMC5/6 complex ring is composed of two coiled-coil SMC heterodimers SMC5 and SMC6, which associate with a kleisin component, NSMCE4 [2]. The budding yeast Nse5/6 heterodimer is a component of the Smc5/6 complex (essential for proliferation in budding yeast, but not in fission yeast) and has single-stranded (ss) DNA-binding activity [6]. SLF1 and SLF2 physically link RAD18 to the SMC5/6 complex, defining a pathway for SMC5/6 recruitment to sites of DNA damage [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
