Article
MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells
Author/s | Sakellariou, Despoina
Bak, Sara Thornby Isik, Esin Barroso Ceballos, Sonia Inés Porro, Antonio Aguilera López, Andrés Bartek, Jiri Janscak, Pavel Peña Díaz, Javier |
Department | Universidad de Sevilla. Departamento de Genética |
Publication Date | 2022 |
Deposit Date | 2022-04-19 |
Published in |
|
Abstract | Up to 15% of human cancers maintain their telomeres through a telomerase-independent mechanism, termed “alternative lengthening of telomeres” (ALT) that relies on homologous recombination between telomeric sequences. ... Up to 15% of human cancers maintain their telomeres through a telomerase-independent mechanism, termed “alternative lengthening of telomeres” (ALT) that relies on homologous recombination between telomeric sequences. Emerging evidence suggests that the recombinogenic nature of ALT telomeres results from the formation of RNA:DNA hybrids (R-loops) between telomeric DNA and the long-noncoding telomeric repeat-containing RNA (TERRA). Here, we show that the mismatch repair protein MutSβ, a heterodimer of MSH2 and MSH3 subunits, is enriched at telomeres in ALT cancer cells, where it prevents the accumulation of telomeric G-quadruplex (G4) structures and R-loops. Cells depleted of MSH3 display increased incidence of R-loop-dependent telomere fragility and accumulation of telomeric C-circles. We also demonstrate that purified MutSβ recognizes and destabilizes G4 structures in vitro. These data suggest that MutSβ destabilizes G4 structures in ALT telomeres to regulate TERRA R-loops, which is a prerequisite for maintenance of telomere integrity during ALT. |
Project ID. | DFF-4004-00117
R72- A4181-13-S2 310030_184716 19-07674S 19-21325S 200C0060590 VR-MH 2014-46602- 117891-30 170176 ERC2014 AdG669898 TARLOOP PID2019-104270GB-I00/BMC |
Citation | Sakellariou, D., Bak, S.T., Isik, E., Barroso Ceballos, S.I., Porro, A., Aguilera López, A.,...,Peña Díaz, J. (2022). MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells. Cell Reports, 39 (1), 110602. |
Files | Size | Format | View | Description |
---|---|---|---|---|
MutSb regulates G4-associated.pdf | 3.778Mb | [PDF] | View/ | |