TY - JOUR
T1 - Human MLH1 suppresses the insertion of telomeric sequences at intra-chromosomal sites in telomerase-expressing cells
AU - Jia, Pingping
AU - Chastain, Megan
AU - Zou, Ying
AU - Her, Chengtao
AU - Chai, Weihang
N1 - Funding Information:
National Institutes of Health (NIH) [R01GM112864] (in part); Ladies Auxiliary VFW Cancer Research Funds (to W.C.). Funding for open access charge: NIH [R01GM112864]. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2016.
PY - 2017/2/17
Y1 - 2017/2/17
N2 - 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.
AB - 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.
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U2 - 10.1093/nar/gkw1170
DO - 10.1093/nar/gkw1170
M3 - Article
C2 - 28180301
AN - SCOPUS:85026718189
SN - 0305-1048
VL - 45
SP - 1219
EP - 1232
JO - Nucleic acids research
JF - Nucleic acids research
IS - 3
ER -