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The SMC5/6 Complex Maintains Telomere Length in ALT Cancer Cells through Sumoylation of Telomere‐Binding Proteins
Author(s) -
Potts Patrick Ryan,
Yu Hongtao
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a655-a
Subject(s) - telomere , sumo protein , telomerase , shelterin , telomere binding protein , microbiology and biotechnology , homologous recombination , rad51 , biology , senescence , dna repair , cancer cell , rad52 , cell division , dna , cell , genetics , cancer , dna binding protein , ubiquitin , gene , transcription factor
Telomeres are proteinaceous, repetitive DNA elements at the ends of chromosomes that are shortened after every cell division. Critically short telomeres result in cellular senescence. Most cancer cells upregulate telomerase to elongate telomeres and achieve unlimited proliferative potential. Some cancer cells are incapable of telomerase activation and rely on telomeric homologous recombination (HR) to elongate telomeres, known as alternative lengthening of telomeres (ALT). A hallmark of ALT cells is the recruitment of telomeres into PML bodies (APBs). Previously, we have characterized a role for the human SMC5/6 DNA repair complex in promoting sister chromatid HR at double‐strand breaks by recruitment of the cohesin complex. Here we show that the SMC5/6 complex is localized to APBs in ALT cells. SMC5/6‐RNAi inhibits APB formation which blocks telomeric HR, resulting in telomere shortening and senescence in ALT cells. We identify the shelterin telomere‐binding complex components, TRF1, TRF2, TIN2, and RAP1, as substrates for the SMC5/6 complex SUMO ligase, MMS21. Inhibition of TRF1 or TRF2 sumoylation prevents APB formation. Our results suggest that the SMC5/6 complex facilitates APB formation in ALT cells through sumoylation of telomere‐binding proteins and maintains telomere length by promoting telomeric HR. This work was supported by the NIH and Welch foundation.