The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres.
Repair of DNA double-stranded breaks (DSBs) is crucial for the maintenance of genome stability. DSBs are repaired by either error prone non-homologous end-joining (NHEJ) or error-free homologous recombination. NHEJ precedes either by a classic, Lig4-dependent process (C-NHEJ) or an alternative, Lig4-independent one (A-NHEJ). Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by removal of telomere-binding proteins are recognized as DSBs. In this report, we studied which end-joining pathways are required to join dysfunctional telomeres. In agreement with earlier studies, depletion of Trf2 resulted in end-to-end chromosome fusions mediated by the C-NHEJ pathway. In contrast, removal of Tpp1-Pot1a/b initiated robust chromosome fusions that are mediated by A-NHEJ. C-NHEJ is also dispensable for the fusion of naturally shortened telomeres. Our results reveal that telomeres engage distinct DNA repair pathways depending on how they are rendered dysfunctional, and that A-NHEJ is a major pathway to process dysfunctional telomeres.
Rai
Rekha
R
Department of Genetics, MD Anderson Cancer Center, Houston, TX, USA.
Zheng
Hong
H
He
Hua
H
Luo
Ying
Y
Multani
Asha
A
Carpenter
Phillip B
PB
Chang
Sandy
S
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D000089804:Shelterin Complex; D016615:Telomere; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
C495876:ACD protein, human; C544060:Acd protein, mouse; D034961:Antigens, Nuclear; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000089804:Shelterin Complex; C534796:TRF2 protein, mouse; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen