Human MLH1 suppresses the insertion of telomeric sequences at intra-chromosomal sites in telomerase-expressing cells.
Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI. Moreover, TSI requires telomerase activity but is independent of the functional status of p53 and Rb. Lastly, we show that TSI is associated with chromosome instabilities including chromosome loss, micronuclei formation and chromosome breakage that are further elevated by replication stress. Our studies uncover a novel link between MLH1, telomerase, telomere and genome stability.
Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA.
Pingping
P
Jia
Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA.
Megan
M
Chastain
Cytogenetics Laboratory, Department of Pathology, the University of Maryland School of Medicine, Baltimore, MD, USA.
Ying
Y
Zou
School of Molecular Biosciences, Washington State University, Pullman, WA, USA.
Chengtao
C
Her
Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA.
Weihang
W
Chai
D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D043171:Chromosomal Instability; D053903:DNA Breaks, Double-Stranded; D053843:DNA Mismatch Repair; D004251:DNA Transposable Elements; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D000070957:MutL Protein Homolog 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004251:DNA Transposable Elements; C501486:MLH1 protein, human; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C509186:TERT protein, human; D019098:Telomerase; D000070957:MutL Protein Homolog 1