The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response
Abstract
:1. Introduction
2. DNA Damage Response (DDR)
3. TRF2 Post-Translational Modification and Its Involvement with DDR
4. TRF2 Protects Telomeres by Blocking the Activation of DDR
5. TRF2 Inhibits the ATM Kinase
6. TRF2 Involved in Non-Homologous End Joining (NHEJ)
Repair Mechanism | Gene | Known Function | Known Function | Location | Reference (s) |
---|---|---|---|---|---|
ATM Kinase | ATM | Initial sensing of double-strand breaks of DNA | TRF2 inhibits the activation (autophosphorylation) of ATM on S1981 at the telomeres | Telomeres and non-telomeric regions | [12,104,125] |
γH2AX | Recruitment and activation of other DNA repair factors | TRF2 localized at the same site upon DSB induction | Non-telomeric regions | [104,126] | |
Cell Cycle | pChk2 | Cell cycle regulation | Inhibited by TRF2 via ATM kinase inhibition | Telomeres and non-telomeric regions | [102,127,128] |
MRE11 | Part of the Mre11-Rad50-Nbs1 (MRN) complex to facilitate DNA damage repair | Mediates the maintenance of t-loop and DNA repair at the telomeres with TRF2/RAP1 | Telomeres and non-telomeric regions | [129,130] | |
Apollo (SNM1B) | Involved in the repair of DNA lesions | Localization at the telomeres is TRF2-dependent | Telomeres | [131,132] | |
Direct interaction with endogenous TRF2 | [133] | ||||
Rap1 | Regulation of telomere structure and integrity | Interacts with TRF2 to inhibit NHEJ | Telomeres | [3] | |
Ku70/80 | Initiates and is required for c-NHEJ and suppresses alt-NHEJ | Interacts with TRF2 to inhibit c-NHEJ | Telomeres and non-telomeric regions | [119,134,135] | |
DNA-PK | DNA double-strand break repair complex | Inhibited by TRF2 to prevent c-NHEJ | Telomeres and non-telomeric regions | [136] | |
53BP1 | Early response to DNA double-strand breaks | Localization at DSB induced by inhibition of TRF2 | Telomeres and non-telomeric regions | [53,120,137] | |
BER | pol β | Base-excision repair | Physically bound to TRF2 at the NH2-terminal and COOH-terminal domains | Telomeres and non-telomeric regions | [138,139,140] |
FEN1 | Base-excision repair | Physically bound to TRF2 at the NH2-terminal and COOH-terminal domains | Telomeres and non-telomeric regions | [139,140] | |
APE1 | Base-excision repair | Indirectly stimulated by TRF2 | Telomeres | [136] | |
Lig1 | Base-excision repair | Indirectly stimulated by TRF2 | Telomeres | [140] | |
PARP1 | DNA nick sensor activated rapidly and transiently in response to DNA damage | Recruits TRF2 at DNA damage site | Non-telomeric regions | [92,97] | |
Others | LAP1 | A lamina-associated protein that was recently found to be involved in DDR | Forms a complex with TRF2 upon DNA damage induction and binds at DNA damage site | Non-telomeric regions | [141] |
RTEL1 | A helicase essential in DDR | Recruited by TRF2 at telomeres to promote t-loop unwinding | Telomeres and non-telomeric regions (not TRF2-dependent) | [142,143,144] |
7. TRF2 Interacts with Factors of Base Excision Repair (BER)
8. TRF2 Involvement in the DDR Outside of the Telomeres
9. Other Known Extra-Telomeric Functions of TRF2
10. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Modification | Amino Acids | Modifying Enzymes | Function | Reference (s) |
---|---|---|---|---|
Phosphorylation | Ser20 | Chk2 | Phosphorylation of TRF2 by Chk2 decreases TRF2 binding to telomeric DNA. S20 phosphorylation is required for TRF2 interaction with G-rich RNA and recruitment of ORC to OriP. | [74,75] |
Ser365 | CDK | Regulates the assembly and disassembly of t-loop during the cell-cycle or DNA replication, which protects the telomeres from replicative stress. | [69] | |
Thr188 | ATM | Early recruitment at the DNA break site and may be involved in DNA damage response/repair. | [72,95] | |
Thr358 | Aurora C | Possible function in cell replication and unwinding of the chromosome. | [96] | |
SUMOylation | IK140TE, LK245SE, and RK333DE | MMS21 | Stabilization of TRF2 and recruitment at the telomeres. | [79,80] |
- | PIAS1 | Interacts with RNF4 to regulate TRF2 level at the telomeres. | [78] | |
Ubiquitylation | K173 K180 K184 | Siah1 | Siah1 is a p53-inducible E3 ligase with a C3H4-type RING finger domain. Knockdown of Siah1 stabilizes TRF2 and telomere length maintenance. | [85] |
- | RNF4 | Interacts together with PIAS1 in modulating TRF2 role in telomere maintenance and protection through regulating the level of TRF2 at the telomeres. Acts downstream of the ATM-kinase pathway in DDR. | [78,84] | |
Acetylation | K293 | P300 | Required for TRF2 stabilization and efficient binding at the telomeres. | [86] |
Poly(ADP-ribosyl)ation or PARsylation | - | PARP1, PARP2 | Reduces the binding of TRF2 to telomeres that may contribute to dysfunctional telomeres. | [92,97] |
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Imran, S.A.M.; Yazid, M.D.; Cui, W.; Lokanathan, Y. The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response. Int. J. Mol. Sci. 2021, 22, 9900. https://doi.org/10.3390/ijms22189900
Imran SAM, Yazid MD, Cui W, Lokanathan Y. The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response. International Journal of Molecular Sciences. 2021; 22(18):9900. https://doi.org/10.3390/ijms22189900
Chicago/Turabian StyleImran, Siti A. M., Muhammad Dain Yazid, Wei Cui, and Yogeswaran Lokanathan. 2021. "The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response" International Journal of Molecular Sciences 22, no. 18: 9900. https://doi.org/10.3390/ijms22189900