The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins.
Most cancer cells activate telomerase to elongate telomeres and achieve unlimited replicative potential. Some cancer cells cannot activate telomerase and use telomere homologous recombination (HR) to elongate telomeres, a mechanism termed alternative lengthening of telomeres (ALT). A hallmark of ALT cells is the recruitment of telomeres to PML bodies (termed APBs). Here, we show that the SMC5/6 complex localizes to APBs in ALT cells and is required for targeting telomeres to APBs. The MMS21 SUMO ligase of the SMC5/6 complex SUMOylates multiple telomere-binding proteins, including TRF1 and TRF2. Inhibition of TRF1 or TRF2 SUMOylation prevents APB formation. Depletion of SMC5/6 subunits by RNA interference inhibits telomere HR, causing telomere shortening and senescence in ALT cells. Thus, the SMC5/6 complex facilitates telomere HR and elongation in ALT cells by promoting APB formation through SUMOylation of telomere-binding proteins.
Potts
Patrick Ryan
PR
Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9041, USA.
Yu
Hongtao
H
D018797:Cell Cycle Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone; D006801:Humans; D008025:Ligases / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D011995:Recombination, Genetic; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000235:genetics*; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C432931:SMC5 protein, human; C432932:SMC6 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D008025:Ligases; C503501:NSMCE2 protein, human