Cockayne Syndrome group B protein interacts with TRF2 and regulates telomere length and stability.
The majority of Cockayne syndrome (CS) patients carry a mutation in Cockayne Syndrome group B (CSB), a large nuclear protein implicated in DNA repair, transcription and chromatin remodeling. However, whether CSB may play a role in telomere metabolism has not yet been characterized. Here, we report that CSB physically interacts with TRF2, a duplex telomeric DNA binding protein essential for telomere protection. We find that CSB localizes at a small subset of human telomeres and that it is required for preventing the formation of telomere dysfunction-induced foci (TIF) in CS cells. We find that CS cells or CSB knockdown cells accumulate telomere doublets, the suppression of which requires CSB. We find that overexpression of CSB in CS cells promotes telomerase-dependent telomere lengthening, a phenotype that is associated with a decrease in the amount of telomere-bound TRF1, a negative mediator of telomere length maintenance. Furthermore, we show that CS cells or CSB knockdown cells exhibit misregulation of TERRA, a large non-coding telomere repeat-containing RNA important for telomere maintenance. Taken together, these results suggest that CSB is required for maintaining the homeostatic level of TERRA, telomere length and integrity. These results further imply that CS patients carrying CSB mutations may be defective in telomere maintenance.
Department of Biology, McMaster University, 1280 Main St. West Hamilton, ON, Canada L8S4K1.
Nicole L
NL
Batenburg
Taylor R H
TR
Mitchell
Derrik M
DM
Leach
Andrew J
AJ
Rainbow
Xu-Dong
XD
Zhu
D002460:Cell Line; D003057:Cockayne Syndrome / Q000235:genetics*; D004265:DNA Helicases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D062085:RNA, Long Noncoding / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000737:chemistry; D059505:Telomere Homeostasis; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*
D000075223:Poly-ADP-Ribose Binding Proteins; D062085:RNA, Long Noncoding; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D019098:Telomerase; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes